# Modulation of OGG1 enzymatic activities by small molecules, promising tools and current challenges

Xavier Renaudin, Anna Campalans

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Xavier Renaudin, Anna Campalans. Modulation of OGG1 enzymatic activities by small molecules, promising tools and current challenges. DNA Repair, 2025, 149, 10.1016/j.dnarep.2025.103827. hal-05110034

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Submitted on 12 Jun 2025

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# Modulation of OGG1 enzymatic activities by small molecules, promising tools and current challenges

Xavier Renaudin<sup>a,b</sup>, Anna Campalans<sup>a,b,*</sup>

## ARTICLE INFO

Keywords:

- Base excision repair
- OGG1 modulators
- Small molecules
- Oxidative DNA damage
- Transcriptional regulation
- Inflammation
- Cancer

## ABSTRACT

Oxidative DNA damage, resulting from endogenous cellular processes and external sources plays a significant role in mutagenesis, cancer progression, and the pathogenesis of neurological disorders. Base Excision Repair (BER) is involved in the repair of base modifications such as oxidations or alkylations as well as single strand breaks. The DNA glycosylase OGG1, initiates the BER pathway by the recognition and excision of 8oxoG, the most common oxidative DNA lesion, in both nuclear and mitochondrial DNA. Beyond DNA repair, OGG1 modulates transcription, particularly pro-inflammatory genes, linking oxidative DNA damage to broader biological processes like inflammation and aging. In cancer therapy, BER inhibition has emerged as a promising strategy to enhance treatment efficacy. Targeting OGG1 sensitizes cells to chemotherapies, radiotherapies, and PARP inhibitors, presenting opportunities to overcome therapy resistance. Additionally, OGG1 activators hold potential in mitigating oxidative damage associated with aging and neurological disorders. This review presents the development of several inhibitors and activators of OGG1 and how they have contributed to advance our knowledge in the fundamental functions of OGG1. We also discuss the new opportunities they provide for clinical applications in treating cancer, inflammation and neurological disorders. Finally, we also highlight the challenges in targeting OGG1, particularly regarding the off-target effects recently reported for some inhibitors and how we can overcome these limitations.

## 1. Introduction

Oxidative DNA damage is caused by endogenous cellular processes such as respiration, hydrolysis, and increased levels of reactive oxygen species (ROS) resulting from an imbalance between their production and detoxification [1]. Additionally, ROS are produced by exogenous sources, including cancer treatments such as chemotherapy or radiotherapy. Oxidative DNA lesions are estimated to occur at a rate of $10^4$ per cell per day, including single-base modifications, single- or double-strand breaks, intra- or inter-strand crosslinks, and DNA-protein crosslinks [2, 3]. If unrepaired, these DNA damages can become a significant source of mutations. Large-scale sequencing has highlighted that these lesions, particularly single-base modifications, are significant mutagenic contributors in cancer cells, giving rise to several mutational signatures [4–6]. Importantly, oxidative DNA damage participates in neurological disorders and is associated with aging phenotype.

Base Excision Repair (BER) is a highly conserved DNA repair system responsible for detecting and repairing oxidative DNA damage [7].

Around 30 proteins participate in BER that is typically described as a two-branch DNA repair pathway, initiated by the detection and excision of the damaged base by a DNA glycosylase specific to the lesion followed by the removal of one (short-patch BER) or several (long-patch BER) nucleotides. Following the activity of these DNA glycosylases, an abasic site is formed and further processed by the action of apurinic/apyrimidinic endonuclease 1 (APE1), which cleaves the phosphodiester backbone at the 5' site, forming a single-strand break (SSB). Subsequently, a cascade of enzymatic reactions involving various DNA polymerases (POL β, δ, ε, and possibly λ [8,9]) and DNA ligase I and III completes the repair process. In humans, there are eleven DNA glycosylases that are specific, yet often redundant, for different types of lesions. Among these glycosylases, is the 8-oxoG glycosylase 1 (OGG1), which is responsible for detecting and removing the most abundant oxidative DNA lesion, the 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxoG) in both nuclear [10] and mitochondrial compartments [11–13]. OGG1 belongs to the class of bifunctional DNA glycosylases but has a weak β-lyase activity and therefore requires APE1 for further

<footnote><sup>a</sup> Université Paris-Saclay, iRCM/IBFJ, CEA, Genetic Stability, Stem Cells and Radiation, Fontenay-aux-Roses F-92260, France</footnote>

<footnote><sup>b</sup> Université Paris Cité, iRCM/IBFJ, CEA, Genetic Stability, Stem Cells and Radiation, Fontenay-aux-Roses F-92260, France</footnote>

<footnote>* Corresponding author at: Université Paris-Saclay, iRCM/IBFJ, CEA, Genetic Stability, Stem Cells and Radiation, Fontenay-aux-Roses F-92260, France.</footnote>

<footnote>E-mail address: anna.campalans@cea.fr (A. Campalans).</footnote>
processing the abasic site generated after excision of the 8-oxoG. The BER is, so far, the major DNA repair pathway that is present into the mitochondria, while only few proteins of other pathways have been reported [14,15]. Additionally to its role in the BER, OGG1 has appeared as a key modulator of transcription. Gene expression analysis of mouse deficient for OGG1 revealed a role of this DNA glycosylase in regulating pro-inflammatory genes [16–19]. These early studies have open the path to new research revealing the role of OGG1 and the 8-oxoG in tran- scription regulation [20,21].

Interestingly, it was proposed several decades ago that inhibiting BER could be an effective strategy to treat cancer by increasing DNA damage and the mutational burden [22]. Since then, several inhibitors targeting almost all the steps of the BER pathway have been developed, some of them showing promising effects in cells, pre-clinical models and clinical trials [23]. Major success in BER inhibition in the clinics came from the treatment of cells or tumours having a deficiency to repair double-strand breaks (DSB) by homologous recombination (HR) pathway, either because of defects in the tumour suppressor genes BRCA1 and BRCA2 or in other genes compromising the HR [24–28]. Nevertheless, while the use either of PARP1 inhibitors or in some extent of APE1 can specifically target such HR-deficient cancer cells, these treatments often give rise to cancer resistance [29], justifying the need to develop new inhibitors of the BER. OGG1 has become an interesting target since the loss of OGG1 sensitizes the cells to chemotherapies [30], radiotherapies [31] and PARP inhibitors [27] showing the promising application of OGG1 inhibitors to potentiate current therapies. In this review, we will specifically address the progress made in targeting the DNA glycosylase OGG1 by using small molecules, the challenges encountered, and the current developments and strategies to overcome these limitations. We will also discuss the most recent findings about the potential use of OGG1 activators in reducing oxidative DNA damage involved in aging and neurological disorders.

## 2. Development of competitive and non-competitive OGG1 inhibitors

Although it was reported as early as 2005 that the free 8-oxoG base inhibited both the DNA-glycosylase and AP-lyase activities of OGG1 [32] it was not until 10 years later that the first small molecule was identified and described as an OGG1 inhibitor. In the search of OGG1 inhibitors, several groups have designed fluorescence-based assays to screen thousands of molecules. To identify the first potent inhibitors of OGG1, the Lloyd's group developed an assay using a DNA duplex con- taining an 8-oxoG lesion located six deoxynucleotides downstream of a TAMRA (5-Carboxytetramethylrhodamine) fluorophore paired to a complementary DNA strand containing a quencher [33]. Upon the addition of increasing amounts of purified OGG1 enzyme resulting in 8-oxoG excision and strand incision, the TAMRA labelled 6-mer is released into the solution, becoming fluorescent in an OGG1 dose-dependent manner. This assay was used to screen 49,840 mole- cules, yielding 214 hits, of which 13 lead compounds were reconfirmed for inhibiting OGG1 activity with IC50 values below 10 µM. Among these lead compounds, O8 and four other molecules were further studied for their specificity towards OGG1 compared to other DNA glycosylases (NEIL1, NTH1, and Fpg) and their lack of side effect on DNA structure. The authors conducted several rounds of experiments to demonstrate that O8 does not inhibit OGG1 recognition of its substrate directly. Instead, gel-shift experiments revealed that O8 inhibits the DNA glyco- sylase and AP-lyase activities of OGG1 during the formation of the Schiff base consequently trapping the enzyme on the DNA substrate. Indep- endently, by real-time live imaging we have monitored the subnuclear dynamics of OGG1 tagged with a GFP and followed its recruitment and residence time at microirradiation-induced 8-oxoG in the presence or absence of O8 [34]. Upon microirradiation, OGG1 was recruited at the chromatin and quickly released once the repair was completed while it remained accumulated at the lesion in the presence of O8, illustrating

that the inhibitor could affect OGG1 dynamics in living cells (Fig. 1). More studies are needed to further explore whether in the presence of O8 the enzyme is trapped to the chromatin or repetitively recruited to the unrepaired damage.

Another group followed a similar strategy to identify the SU0268 inhibitor [35]. By screening a library of 25,975 molecules, the Kool group identified 22 OGG1 inhibitors. The screening was based on the fluorogenic probe OGR1, in which the 8-oxoG acts as a quencher of a neighboring fluorescent base. Emission of fluorescence occurs after excision of the lesion allowing to quantify OGG1 activity in real time. Surface plasmon resonance experiments confirmed that SU0268 binds to OGG1 independently of the DNA substrate. Like the O8, SU0268 showed high specificity towards OGG1, did not affect other DNA repair enzymes (such as MTH1, dUTPase, NUDT16, or SMUG1), and was well tolerated in cells.

To identify OGG1 inhibitors, the Helleday lab employed similarly a duplex oligonucleotide containing an 8-oxoG substrate that release a fluorophore in the presence of purified OGG1 and APE1 proteins [36]. They screened a library of 17,940 molecules and identified one hit, TH5487, which was refined to an inhibitory concentration of 342 nM and demonstrated specificity for OGG1 without affecting other DNA glycosylases (Fpg, MPG, NEIL1, UNG2, TDG, SMUG1 or APE1). The authors convincingly showed that the inhibitor works in cells by delaying the repair of 8-oxoG lesions induced by potassium bromate (KBrO₃) treatment, impairing the recruitment of OGG1 to its genomic substrate. Further studies using laser microirradiation for the local in- duction of oxidative DNA damage have confirmed that TH5487 treat- ment reduces OGG1 recruitment to 8-oxoG [34,37] (Fig. 1). Interestingly, since 8-oxoG plays a key role in regulating transcription initiation, the authors tested whether TH5487 could reduce the in- flammatory response upon TNFα treatment. They monitored the expression levels of chemokines, including CXCL1, and demonstrated that TH5487 treatment reduced mRNA expression in response to TNFα, both in cellulo and in mice. These findings highlight the efficacy of the inhibitor and its potential usefulness in treating inflammatory diseases. Following this study, the same group had generated derivatives of the TH5487, including the TH8535 showing an optimized interaction with OGG1 and efficiently inducing a significant loss of viability in a panel of cancer cell lines [38]. By crystallography analysis, they showed these inhibitors adopt a chair conformation localizing in the active pocket of the mouse OGG1 protein, structurally similar to the human one (Fig. 2B).

Altogether, the screening of thousands of different molecules has allowed the identification and characterization of several highly potent inhibitors of OGG1. The O8 targets the catalytic activity of the protein without impairing its binding to the 8-oxoG while others inhibitors, namely the TH5487 and its derivatives, the SU0268 and the SU0383 are competitive inhibitors acting by binding directly the catalytic pocket of the enzyme and affecting its recruitment to the DNA lesions (Fig. 1 and Fig. 2).

## 3. Biological effects of OGG1 inhibitors

Many outstanding questions in fundamental research regarding OGG1 function remain unresolved. OGG1 inhibitors are valuable tools for investigating the diverse roles of OGG1, not only in its canonical function as a DNA repair protein but also its more recently identified role in transcriptional regulation. A precise understanding of the molecular mechanisms of OGG1 and the mode of action of OGG1 inhibitors is essential for a successful use of these molecules in therapeutical applications.

### 3.1. OGG1 inhibitors as a tool to induce cancer cell death

The potential application of OGG1 inhibitors for cancer treatment, alone or in combination with other molecules such as PARP inhibitors or
<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Mechanism of action of OGG1 inhibitors. Competitive OGG1 inhibitors TH5487 and SU0268 block OGG1 binding to genomic 8-oxoG, while the O8 does not prevent binding but inhibits the excision of the modified base. The dynamics of OGG1 on oxidized DNA can be followed by real-time imaging upon induction of 8-oxoG by laser microirradiation in living cells. While competitive inhibitors (TH5487) reduce OGG1-GFP recruitment to oxidative lesions, the retention time is much longer in the presence of the excision inhibitor (O8) (graphical representation based from results presented in [34]).</figcaption></figure>

chemotherapeutical agents has been explored during the last few years. OGG1 inhibitors have shown promising effects when used in combination with PARP inhibitors in cells that are mutated for BRCA1 gene in ovarian and breast cancer [27], or with the chemotherapeutical agent methotrexate [39]. The authors of those studies hypothesized that inhibition of OGG1 could promote the accumulation of single and double strand breaks leading to cell death. Importantly, the assumption that OGG1 inhibitors will target cancer cells by increasing DNA damage and particularly the load of SSB and DSB must be carefully evaluated.

Previous studies have shown that the activity of OGG1 and by extension the BER pathway generate DNA repair intermediates such as SSB that can overactivate PARP1. Indeed, cells deficient in OGG1 or expressing OGG1 mutants without enzymatic activity, generate reduced levels of single and double strand DNA breaks upon exposure to oxidative stress. Consequently, a decreased PARP1 activation and cell death mediated by parthanatos was reported in those cells [40]. In agreement with these observations, the inhibition of OGG1 by TH5487 has been shown to reduce the formation of 53BP1 and γH2AX foci, in response to potassium bromate, as fewer SSB are generated due to inhibition of the excision activity of OGG1 [37]. In the same line, a downregulation of OGG1 or its inhibition by TH5487, has been demonstrated to negatively affect the therapeutical efficiency of PARP inhibitors in HR deficient cells [41]. Importantly, these effects could be extrapolated to a reduced BER efficiency that could be also induced by downregulation of MUTYH, which excises the A in front of the 8-oxoG, or treatment with ROS scavengers resulting in a reduction of oxidative DNA damage.

TH5487 has been shown to arrest proliferation of a panel of cancer cells [30]. In this study, treatment of cells with the competitive OGG1 inhibitor results in the formation of DSB during S-phase and replicative stress. However, the levels of 8-oxoG measured in the cells exposed to TH5487 for up to 120 hours remained very low and therefore the formation of DSB was not necessarily due to the accumulation of BER intermediates but most likely to an indirect effect. Indeed, a transcriptional downregulation of replication genes was also observed in the same study that could lead to replication stress and genome instability.

One possible explanation for this discrepancy is the genomic context in which OGG1-induced lesions occur. Indeed OGG1 has been shown to be required for the repair of radiation induced clustered DNA damage

[31] and it cannot be excluded that in G-rich regions, such as telomeres or promotors, OGG1 inhibition could favour DSB formation. Further studies are needed to understand the molecular mechanisms behind the effect of OGG1 inhibitors on cancer cell proliferation. Besides the genetic context such as mutations in BRCA genes or the status of the TP53 protein, an important limitation of the use of the inhibitor is the expression level of the targeted protein. In some cancers, the expression levels of DNA glycosylases such as OGG1 are reported to be low, which may reduce the effectiveness of the inhibitors.

## 3.2. OGG1 inhibitors affect transcriptional regulation

Multiple independent studies have demonstrated the usefulness of OGG1 inhibitors in reducing the expression of pro-inflammatory genes and their potential use as a therapeutic strategy for the treatment of inflammatory diseases has been recently reviewed elsewhere [42,43]. Molecularly, how OGG1 participates in the regulation of transcription remains an intense field of research. It is widely accepted that in response to several stimuli generating ROS, induction of 8-oxoG at promoters and recruitment of OGG1 are essential for the establishment of complex transcriptional programs including the expression of hypoxia-responsive genes, genes involved in the epithelial-mesenchymal transition or the inflammatory response [20,21, 44]. The binding of OGG1 to the promotors of several genes involved in the inflammatory response, including TNFα and Cxcl-2 has been reported, and the inhibition of OGG1 by TH5487 was shown to be sufficient to decrease their expression [36]. Importantly, it has been established that the enzymatic activity of OGG1 was dispensable to regulate inflammatory gene expression. The mutant of OGG1, K249Q, deficient for the excision activity of OGG1 was still capable to induce gene expression in response to TNFα exposure, at even higher level than the WT form of OGG1 [45]. Moreover, treatment with the TH5487, that inhibit the binding of OGG1 to the DNA, prevents the expression of CXCL1, while the O8 inhibitor that block the glycosylase activity and tend to attach OGG1 to the chromatin was fully capable to activate transcription. This confirms by an independent strategy that OGG1 presence but not its activity was necessary to regulate gene expression [45].

In response to respiratory syncytial virus (RSV), it has been
<figure><img src="image_6.png" /><figcaption>**Fig. 2.** Current known inhibitors of OGG1. Domains of OGG1 (upper part) with key amino-acids for 8-oxoG recognition and DNA glycosylate activity highlighted in pink. Mitochondrial Targeting Signal (MTS) and Nuclear Localization Signal (NLS) are indicated in green. The HhH domain is indicated in blue. A. Human OGG1 crystal structure (PDB ID= 6W13) showing the binding of TH5487 in the active pocket of the enzyme. Key amino-acids are indicated in pink and the HhH domain is in blue. Structure has been displayed using the PyMOL software (https://www.pymol.org/). B. Chemical Structure of currently known OGG1 inhibitors O8, TH5487 and SU0268. The dual inhibitor SU0383 targeting both OGG1 and MTH1 is also represented.</figcaption></figure>

established that ROS induce the excessive activation of the innate immune response by a two steps mechanism: by generating 8-oxoG at regulatory gene sequences but also by inhibiting OGG1 repair activity. The authors of the study hypothesized that oxidation of OGG1 cysteines, previously shown to inhibit its enzymatic activity [46], could represent a finely tuned regulatory mechanism preventing the repair of 8-oxoG and inducing gene expression. Inhibition of OGG1 binding to the DNA by treatment with TH5487, decreases this excessive expression [47]. OGG1 was further shown to be required for the recruitment of transcription factors, including SMAD3 and STAT1, resulting in the induction of fibrotic and inflammatory gene expression and inhibition of its recruitment by the TH5487 or SU0268 was sufficient to abrogate these responses [48,49].

While technically challenging [50], the mapping of the 8-oxoG in different conditions, such as hypoxia, normoxia or under oxidative stress is surprisingly consistent. Indeed, ChIP-seq analysis, OG-seq, enTRAP-seq but also immunofluorescence analysis show that 8-oxoG tend to accumulate in euchromatin regions and particularly at transcription regulatory regions, including promoters, 5'-UTR and 3'-UTR sequences

[51–54]. Moreover, several studies have shown that 8-oxoG act as a regulator of G-quadruplex (G4) formation enhancing the recruitment of transcription factors when formed in cis of the promotor or decreasing their recruitment when formed in trans [44,55]. It has been reported that oxidation and formation of 8-oxoG at a G4 forming sequence in the VEGF promoter affects the folding of the G4 secondary structure. While the presence of 8-oxoG in the coding strand was sufficient to increase the expression of VEGF, oxidation of the template strand lead to a strong expression decrease. However in this case, enzymatic activities of OGG1 and APE1 were shown to be essential and no effect on gene expression was observed in OGG1 deficient cells [55]. Interestingly, by using reporter plasmids bearing 8-oxoG in the sequence of several viral and human promoters, the Khobta lab demonstrated that the BER intermediates generated by OGG1 and APE1 activities induced a strong transcriptional arrest [56]. Furthermore, it remains unclear if the recognition of the 8-oxoG by OGG1 is required for transcriptional regulation and it has been suggested in a recent study comparing gene expression induced by H₂O₂ treatment in WT cells and in OGG1 or MUTYH deficient cells that the 8-oxoG itself could be a signal of cellular
stress independently of its repair [57]. The effects of 8-oxoG and OGG1 on transcriptional induction or repression appear to depend on the genomic context and given the importance of this regulation, they are likely finely tuned by specific molecular mechanisms that are not yet completely understood.

Concomitantly besides the action of OGG1 inhibitors on the enzymatic activity of the enzyme, they also affect the protein dynamics and its capacity to be recruited to the chromatin upon induction of oxidative DNA damage [34,36,37]. In this regard, it is important to understand in detail the molecular mechanisms leading to OGG1 recruitment to euchromatin regions. Of note, it is has been shown that the chromatin itself plays a role to regulate the access of OGG1 to the lesion. Indeed, while OGG1 can bend DNA and extrude the G or 8-oxoG bases on naked DNA [58] the base is not flipped out when it is located at nucleosomal internal sites [59]. In agreement with this observation, OGG1 activity is reduced on nucleosome but the addition of the SWI/SNF chromatin remodelers significantly increase its activity [60]. In response to oxidative stress, OGG1 has been found to be associated to cohesin and mediator complexes, essential for the tridimensional organisation of the genome and the transcriptional regulation [61]. This interaction is required for the positioning of OGG1 at DNA lesions and the repair of 8-oxoG. It is tempting to speculate, that in response to local increase of oxidation, the same complexes can participate to the recruitment of OGG1 and the regulation of gene expression, although such model requires further investigations. A crosstalk between BER and nucleotide excision repair (NER) has also been reported [62]. It has been established by in vitro analysis that the NER protein, UV-damaged DNA binding protein (UV-DDB, composed of DDB1 and DDB2) has a high affinity to bind 8-oxoG and stimulates the excision activity of OGG1 and APE1 (three and eight-fold respectively) [63,64]. Single-molecule analysis of DNA binding proteins using C-trap confirms the role of UV-DDB in stimulating the recruitment of OGG1 [65]. At telomeres, DDB2 recognizes the 8-oxoG and facilitates chromatin relaxation, allowing the recruitment of OGG1 and XPC at the damaged sites [66]. At transcription active regions, DDB2 is not required but the other NER factors can intervene to facilitate the removal of BER intermediates [64]. Altogether, these studies highlight different proteins that can facilitate the recruitment of OGG1 to euchromatin or telomere regions. If OGG1 inhibitors affect the interaction of OGG1 with some of its partners remains to be explored.

Although many studies have highlighted the crucial role of OGG1 in transcriptional regulation, the molecular mechanisms behind its recruitment to chromatin and its impact on gene expression are not fully understood and it remains unclear if the enzymatic activity is required or not. Further research is needed to determine whether the different proposed mechanisms coexist, and if they are dependent on the genomic context or specifically involved in the regulation of particular set of genes. This fundamental understanding is essential for identifying situations in which the effect of OGG1 inhibitors on transcription could offer therapeutic benefits, in particular for the treatment of inflammatory diseases.

## 4. Off-target effects of the OGG1 inhibitors

It is important to emphasize that despite these promises, OGG1 inhibitors present several off-target effects that are important to consider before proceeding further into preclinical studies. Indeed, lack of efficacy, dose limiting toxicities and off-target effects are the major drawbacks for many molecules in oncology that fail to advance to clinical assay leading to a very low approval rate (around 3 %) by the Food and Drug Administration in the US [67,68].

### 4.1. Competitive OGG1 inhibitors TH5487 and SU0268 directly inhibit efflux pumps

We have recently reported that treatment with two OGG1 inhibitors,

the TH5487 and the SU0268, increase the intracellular accumulation of several fluorescent dyes classically used to stain the nucleus or the mitochondria [69]. The same observations were made in OGG1 knockout cells generated by CRISPR/CAS9, suggesting they were necessarily due to an off-target effect of the molecules. Surprisingly, the effect of OGG1 inhibitors were very similar to the ones observed with verapamil, a molecule that inhibits efflux pumps and is classically used to improve the staining with dyes that are efficiently expelled from the cell by the action of these transporters. Efflux pumps are a superfamily of 48 ATP-binding cassette transport proteins, localized at the plasma membrane, that facilitate the efflux of not only dyes but also chemo-therapeutic molecules, and their overexpression is associated with cancer cell resistance to several chemotherapies [70]. To evaluate if OGG1 inhibitors could directly inhibit efflux pumps, we used an in vitro vesicle transport assay to test the effect of the molecules on the most characterized efflux pumps proteins, namely ABCB1/MDR1 (multidrug resistance 1), ABCC1/MRP1 (multidrug resistance-associated protein 1) and ABCG2/BCRP (Breast-cancer resistance protein). Importantly, we demonstrated that, at the standard dose of 10 µM, TH5487 inhibit completely BCRP and mildly MDR1 and MRP1 while the SU0268 strongly inhibits BCRP and MDR1, and mildly MRP1. The effects of OGG1 competitive inhibitors on efflux pumps should be taken into consideration in the interpretation of previous observations made with TH5487, suggesting synergistic effects of the molecule with PARP inhibitors or methotrexate [27,39]. While mechanistically it was proposed that TH5487 could induce a higher generation of single and double-strand breaks, one can question whether these effects could be due to a higher concentration of drugs that would be retained by the cells due to the direct inhibition of efflux pumps by the OGG1 inhibitor. In line with this hypothesis, a higher induction of DSB was measured in treatments combining etoposide and OGG1 inhibitors TH5487 and SU0268, compared to etoposide alone, as observed with the general efflux pump inhibitor Verapamil [69]. Since the combined effects between OGG1 inhibitors and methotrexate or PARP inhibitors were not evaluated in OGG1 deficient cells, further studies are required to conclude between the two possibilities.

These effects represent a major limitation in the use of OGG1 competitive inhibitors in both fundamental research and clinical applications. While there has been a significant interest in blocking efflux pumps to reduce multidrug resistance and improve the efficacy of chemotherapy, no promising results have emerged from the many specific inhibitors developed during the last decades. This is mainly due to the toxicity of these molecules and the poor response caused by the multiple efflux pumps expressed by cancer cells [71]. Mechanistically it remains surprising that two chemically unrelated compounds, TH5487 and SU0268, which were designed to fit in the active pocket of OGG1, could directly inhibit efflux pumps. Future studies, particularly crystal structure analysis or molecular docking techniques will be crucial to determine whether there are some common features between OGG1 and efflux pumps surfaces that might limit the use of small molecules targeting the active site for specifically inhibit OGG1.

### 4.2. Competitive inhibitor SU0268 affects microtubule network

In the same work [69], we also established that the SU0268 was having additional off-target effect, by impairing mitotic progression, independently of OGG1. Indeed, we measured cell proliferation in presence of both inhibitors, TH5487 and SU0268, in wild-type cells or in OGG1 deficient cells and observed, in presence of TH5487, a slight decrease of cell proliferation, independent of OGG1. However, most importantly, in presence of SU0268, we could observed a strong proliferation arrest, in WT cells or in OGG1 deficient cells, pointing out again to an off-target effect. We demonstrated that the SU0268 was capable to arrest cell cycle progression in mitosis, similarly to the nocodazole and to the TH588 that inhibits MTH1 proteins but also microtubule formation [72,73]. Since both OGG1 and MTH1 inhibitors
have an effect on mitotic progression, one could hypothesize that the accumulation of 8-oxoG could be determinant of mitotic fate. However, since the TH5487, that significantly impairs the repair of 8-oxoG [36, 69], has no effect on mitosis, this remains unlikely.

## 5. Development of dual inhibitors for an efficient targeting of the GO system

A dual inhibitor targeting both OGG1 and the MutT Homolog 1 (MTH1) enzyme has also been developed [74]. MTH1 is a protein that hydrolyzes the oxidized pool of dNTP, notably the dGTP and carry with OGG1 the surveillance and repair of most of the 8-oxoG lesions in the cells. In human cells, OGG1 and MTH1, together with the DNA-glycosylase MUTYH, a DNA-glycosylase that removes the adenine when it is mis-incorporated in front of 8-oxoG, giving a second chance to OGG1 to repair the lesion, constitute the so called GO system that is dedicated to limit the mutagenesis associated to the 8-oxoG [75,76].

Based on promising cytotoxic effects of MTH1 inhibitors in cancer cells, partially attributed to the higher incorporation of oxidized dNTPs [73], the Kool group assumed that targeting both OGG1 and MTH1 with one single molecule could significantly improve the cytotoxic effect of the inhibitor by increasing genomic oxidative DNA damage. By studying the structure of well-known inhibitors of MTH1 (the TH287 and the IACS-4759) and the structure of the SU0268, the authors designed two strategies to develop a dual inhibitor [74]. Firstly, they merged the two compounds (TH287 with the SU0268) by replacing a non-pharmacophore domain of the SU0268 by one domain of the MTH1 inhibitor; secondly, they coupled the two molecules (the IACS-4759 with the SU0268) by adding a linker between them. By testing the various molecules obtained, the authors established that the linker strategy was the best to retain both inhibitory activities against OGG1 and MTH1 enzymes. Further refinement of the linker, lead to the generation of SU0383 that has a strong dual activity against OGG1 and MTH1. As hypothesised, the SU0383 was shown to sensitize cells to oxidative stress more efficiently than the SU0268 [74].

Although the dual inhibition of both OGG1 and MTH1 has shown promising effects, other studies have shown that blocking OGG1 with SU0268 has reduced efficacy in lung adenocarcinoma cells lacking MTH1 compared to wild-type cells. These MTH1-deficient cells showed fewer DSB and lower sensitivity to SU0268. Based on their genetic and inhibitor studies, the authors concluded that co-inhibiting OGG1 and MTH1 may not provide significant tumor-suppressive benefits. They suggested that this co-inhibition might actually protect tumors by preventing DNA breaks induced during BER that rely on the enzymatic activities of the DNA glycosylases [77]. The potential benefits of targeting MTH1 alone or in combination with OGG1 for cancer therapy requires further investigation. Indeed, several MTH1 inhibitors have been developed and while the first generation of molecules showed promising inhibitory effects on tumor cell proliferation [73,78] highly selective and potent inhibitors failed to show any cytotoxicity [79,80]. These findings, along with evidence that the effects of first-generation MTH1 inhibitors persisted in MTH1-depleted cells and that tubulin was identified as a primary target, suggest that their cytotoxicity may stem from off-target effects [81]. Thus, while MTH1 inhibitors hold promise for cancer treatment, with several currently in clinical trials, their molecular mechanisms of action and potential off-target effects must be thoroughly examined to evaluate their clinical therapeutic potential [82].

Although to our knowledge, no specific small-molecule inhibitors targeting MUTYH glycosylase are available, silencing MUTYH expression using siRNA has been shown to reduce pancreatic cancer cell proliferation and increase sensitivity to chemotherapy [83]. Depletion of both OGG1 and MUTYH as well as treatment of MUTYH cells with the OGG1 inhibitor TH5487, partially rescue the proliferation defects induced by exposure of cells to acute oxidative DNA damage at telomeres. Mechanistically, impairing the processing of 8-oxoG at telomeres

by blocking the action of OGG1 and MUTYH, and therefore the generation of SSB as BER intermediates, could allow cells to escape from telomere-mediated senescence but potentially give rise to genome instability and cellular transformation [84]. Therefore, the combined effects of OGG1 inhibitors and MUTYH deficiency are complex and may be context-dependent. Further research is necessary to fully understand the implications of OGG1 inhibition in MUTYH-deficient backgrounds and to assess the potential therapeutic benefits or risks associated with the inhibition of both enzymes. Considering that mutations in the MUTYH gene have been associated with increased cancer risk, particularly colorectal cancer, there is an interest to identify and develop inhibitors specifically targeting MUTYH. Crystal structures have brought major fundamental insights concerning key interactions between the enzyme and the lesion that are essential for the recognition and excision of the adenine paired to an 8-oxoG. Disruption of this interaction by small molecules may provide an original strategy to medical chemists for the development of MUTYH selective inhibitors.

Further research is required to better understand the potential use of simultaneous or individual inhibitors against OGG1, MTH1 and/or MUTYH. Development of new single or dual inhibitors and a better characterization of the existing ones could not only open new therapeutic opportunities but also contribute to our understanding of the particular contributions of the three components of the GO system in safeguarding genome stability and cell fate (Fig. 3).

## 6. Development and potential therapeutic use of OGG1 activators

To mitigate oxidative DNA damage, the development of small molecules that enhance the efficiency of the BER pathway, particularly through OGG1 activation, has emerged as a promising strategy.

Using a fluorescent reporter system, the Bohr group identified and validated the efficacy of different compounds (named A to F) in cellular models by pre-treating cells for 4 hours with the molecules before inducing 8-oxoG with paraquat, a highly toxic herbicide. They observed for all but one (compound C) a lower induction of 8-oxoG [85]. Interestingly, the same compound C was resynthesized and rebranded TH10785 by the Helleday lab [86]. They showed it interacts directly with two amino acids of OGG1 (Phe-319 and Gly-42) within its catalytic site [86]. A fine biochemical characterization of the effects of TH10785 on OGG1 enzymatic activity unveiled that while the molecule was not affecting the DNA glycosylase activity, it was increasing the β-lyase activity and importantly conferring a novel β,δ-lyase activity to the enzyme. Treatment with TH10785 enhanced OGG1 recruitment to sites of oxidative DNA damage, resulting in faster repair of DNA lesions. These findings highlights the therapeutic potential of TH10785 in enhancing genome stability under oxidative stress conditions and treatment of oxidative stress-related disease [87,88]. Interestingly, the repair intermediates generated by the activation of the OGG1 β,δ-lyase activity are dependent on polynucleotide kinase phosphatase (PNKP1), an enzyme required to process products generated by the β,δ-lyase activity of bifunctional DNA glycosylases such as NEIL1-3. Therefore, the combination of TH10785 with PNKP1 inhibitors results in the accumulation of breaks, the activation of the DNA damage response and cell death. Refinement of TH10785 allowed the development of the TH12117 [89] that only enhances the β-lyase activity of OGG1 without creating a new δ-lyase, generating intermediates that can be further processed by APE1 and then the canonical BER, illustrating the potential of fine-tuning specific enzymatic activities to open new therapeutic strategies.

Several OGG1 activators have been identified and shown to preserve mitochondrial function in cells exposed to paraquat [85,90]. Mitochondrial dysfunction induced by this molecule generating oxidative stress was attenuated in the presence of OGG1 activators that could significantly reduce the accumulation of oxidative DNA damage in mtDNA and translocation of cytochrome C indicating the capacity of the
<figure><img src="image_7.png" /><figcaption>**Fig. 3. The GO system and its modulators.** Oxidative stress can oxidize free or incorporated dGTP, potentially leading to transversion mutations after two cycles of DNA replication. The GO system, comprising OGG1, MTH1 and MUTYH, counteracts this mutagenic process. OGG1 excises incorporated 8-oxoG, MTH1 process the oxidized dGTP in the nucleotide pool and MUTYH removes misincorporated adenine, providing a second chance to OGG1. Known inhibitors and activators of the GO system are indicated. Structure of the GO proteins are indicated and have been displayed using PyMOL (PDB 8FAY (MUTYH); 8I8T (MTH1); 6RLW (OGG1)).</figcaption></figure>

molecules to improve integrity of mtDNA and mitochondrial membrane. OGG1 activators were also shown to preserve ATP production and mitochondrial dynamics [85,90]. These observations are in agreement with many studies showing a mitochondrial dysfunction in OGG1 deficient cell models that could be complemented by the overexpression of a mitochondrially targeted OGG1 preventing loss of mitochondrial membrane potential, accumulation of mitochondrial ROS and fragmentation of the network [11,91,92].

The evidences showing that OGG1 could reduce mtDNA damage and prevent apoptosis, suggest a protective role for the protein under oxidative stress conditions [12]. An additional study demonstrated that sirtuin 3 (SIRT3) deacetylates OGG1 stabilizing the protein and controlling its activity. Lack of this regulation induces greater apoptosis in response to DNA damage, with accumulation of 8-oxoG and deletions in mtDNA [93]. Consequently, mtDNA mutations that accumulate during aging were hypothesized to result from oxidative DNA damage. However, deep sequencing of mtDNA from mice and cells lacking key BER proteins, such as OGG1 and MUTYH, revealed no increase in mutations, even under conditions of elevated oxidative stress [94]. This challenges the hypothesis that oxidative DNA damage is a significant source of mutations in the mitochondrial genome, and the exact role and mechanism of action of OGG1 within this organelle remains under debate [94]. Since mitochondrial DNA (mtDNA) exists in multiple copies within cells, the urgency to repair mtDNA damage is reduced and the cells have evolved alternative mechanisms, such as exonucleases, to digest damaged mtDNA.

Recent studies have demonstrated that oxidized mtDNA serves as a sentinel of cellular stress by enhancing inflammatory response or increasing repair of nuclear DNA (nDNA) [95–97]. In response to DNA damage, newly synthesized and oxidized mtDNA is released into the cytosol by the endonuclease FEN1 [98], where it is sensed by cGAS. This, in turn, activates STING and TBK1, triggering the expression of a subset of interferon-stimulated genes (ISGs) such as *PARP9*, *PARP14*, and *ISG15*, which enhance nDNA repair by homologous recombination. This mechanism contributes to the resistance to DNA-damaging agents in

cancer cells [99]. Importantly, mitochondrial OGG1 was shown to repair oxidized mtDNA, thereby counteracting this signaling process [98]. In agreement with this, another study has reported that expression of mitochondrial OGG1 reduces the levels of cytosolic mtDNA and prevents STING mediated inflammation [100]. This mechanism was further expanded to highlight the role of OGG1 in regulating innate immunity. In myeloid cells, oxidative mtDNA activates the inflammasome, leading to the production of IL-1β, IL-18, and cGAS/STING signaling, which subsequently induces ISGs and interferons [101,102].

Modulating this pathway by targeting mitochondrial OGG1 is therefore of great importance. Previous studies have demonstrated the ability of OGG1 inhibitors to reduce inflammation, but they have primarily focused on the nuclear role of OGG1. To our knowledge, the effect of OGG1 inhibitors on mitochondrial function has not been evaluated. It also remains untested whether effect of OGG1 activators on the mitochondria could enhance nDNA repair or gene expression or ameliorate innate immunity, similarly to FEN1 inhibitors [98]. There's a potential interest of OGG1 activators in the treatment of age-related neurodegenerative disorders such as Parkinson or Alzheimer diseases, in which inflammation together with mitochondrial dysfunction plays a critical role in neurodegeneration [103]. In this context it is important to keep in mind that an age-dependent deficiency in the mitochondrial import of DNA glycosylases has been reported [104]. Although further research is required to decipher the molecular mechanisms determining the subcellular distribution of OGG1, a decrease in its mitochondrial localization may reduce the benefit of the OGG1 activators and their potential therapeutic applications.

## 7. Conclusion and future perspectives

Significant efforts have been made to develop OGG1 inhibitors and activators, which hold promise not only for clinical applications but also for advancing our fundamental understanding of the multiple roles of the protein in both the repair of oxidative DNA damage and transcriptional regulation. Promising results have been observed with TH5487
and SU0268 in compromising cancer cell proliferation and reducing the inflammation. Other inhibitors, such as O8 and SU0383, also show potential and will reveal over time whether they live up to expectations. Moreover, the development of OGG1 activators represents a pivotal advancement, as it offers the potential to enhance the enzyme's activity or even to create new functionalities (Fig. 4).

However, our collective progress in developing effective molecules will be hindered unless greater attention is given to their potential side effects. A very precise knowledge on the mechanisms of action of the different molecules, combining knowledge from structural biology and biochemistry together with the validation of cellular effects based on pertinent models is essential. One way to characterize the specific effects is by validating the impact of the molecules on OGG1-deficient cells. Additionally, using cellular models that express only the nuclear or mitochondrial versions of OGG1 is essential for more accurately determining the protein's contribution in each compartment. The molecules should also be tested across a wide range of concentrations and in different cellular backgrounds to ensure their broader applicability. In light of previous observations, particular attention should be given to evaluating the effects of the molecules on efflux pump inhibition and cell cycle progression, comparing these effects with those of previously developed molecules. Additional strategies for inhibiting OGG1 are also

needed. For example, it has been suggested that the photoproteolysis of OGG1 by porphyrins could serve as an alternative approach [105]. This mirrors the more recent development of technologies such as the PRO-teolysis TArgeting Chimeras (PROTAC) that used cellular machineries to degrade specific proteins [106]. These innovative approaches have already shown promising effects by targeting oestrogen receptor, androgen receptor or STAT3 with several currently in clinical trials [107-109].

Another promising strategy could be the development of specific nanobodies, whose structures has been shown to be particularly suited to specifically recognize the catalytic site of enzymes and therefore modulate their enzymatic activity [110]. Considering the unique characteristics of nanobodies such as their small size, high stability and strong affinity for antigen recognition and binding, there is an extensive research for their use in diagnostic and therapeutic applications in cancer therapy and autoimmune diseases with many undergoing clinical trials and some of them already approved for clinical application [111, 112]. Whether such approaches can be used to target essential DNA repair enzymes such as OGG1 remains to be tested.

Another limitation challenging the efficiency of the targeting of OGG1 is the stability of the molecules in the blood. Indeed, TH5487 has been shown to interact with serum proteins, the incubation of the

<figure><img src="image_8.png" /><figcaption>**Fig. 4.** Biological effects of OGG1 inhibitors and activators. OGG1 inhibitors impact DNA repair and transcription in the nucleus. Consequently, an accumulation of DNA damage can be observed, increasing sensitivity to chemotherapeutic agents as long as a decreased expression of pro-inflammatory genes. The effect of the inhibitors on mitochondrial function remains unknown. OGG1 activators enhance nuclear DNA repair and reduce the amount of oxidized mitochondrial DNA released into the cytosol decreasing the inflammatory response. Effects of OGG1 activators on the regulation of transcription remain unknown.</figcaption></figure>
inhibitor with bovine serum albumin resulting in a marked loss of inhibitory capacity on OGG1 activity. The authors suggested that competition between albumin and OGG1 for the binding to TH5487 could reduce the efficacy of the molecule and explain why no effect was observed on tumour growth in a xenograft mouse model, while shRNA targeting OGG1 completely inhibit the growth of the tumor [30]. However, this hypothesis is challenged by the significant effects observed in mice with the same inhibitor on transcriptional regulation and inflammatory response, reported by the same study and many others [21,36,48]. Whatever the reason behind the lack of efficacy of the TH5487 for the targeting of tumoral development, recent advancements in drug vectorization have significantly enhanced the precision and efficacy of therapeutic delivery systems for cancer treatment [113], and it would be interesting to explore if these strategies could help to improve the effects of OGG1 inhibitors.

OGG1 modulators have emerged as highly promising tools, offering significant potential not only to deepen our understanding of the molecular mechanisms underlying OGG1 but also for their future therapeutic applications. The ongoing development of OGG1 inhibitors and activators promises to uncover new insights into DNA repair processes and cellular response to oxidative stress, further enriching the scientific landscape. The near future holds much promise, with potential breakthroughs that could not only enhance our grasp of these fundamental biological processes but also lead to the development of targeted therapies for the treatment of neurodegenerative disorders and cancer.

## Funding

Campalans lab has received financial support from the Agence Nationale de la recherche (ANR-OXIREPTRA and ANR-TIROX), La Ligue contre le Cancer, the graduate school Life sciences and Health (GS-LSH) from the Université Paris-Saclay, Electricité de France and the CEA.

## CRediT authorship contribution statement

**Renaudin Xavier:** Writing – review & editing, Writing – original draft, Conceptualization. **Campalans Anna:** Writing – review & editing, Writing – original draft, Supervision, Funding acquisition, Conceptualization.

## Declaration of Competing Interest

The authors declare that there are no conflicts of interest. There was no financial or non-financial assistance provided by a third party for the reported work. There are no patents or copyrights relevant to this work.

## Acknowledgements

We would like to thank Bertrand Castaing for critical reading of the manuscript and for the many fruitful exchanges concerning OGG1 inhibitors. We are grateful to Anne-Marie Di Guilmi for her help drafting Fig. 2. Campalans lab has received financial support from the Agence Nationale de la recherche (ANR-OXIREPTRA and ANR-TIROX), La Ligue contre le Cancer, the graduate school Life sciences and Health (GS-LSH) from the Université Paris-Saclay, Electricité de France and the CEA.

## Data availability

No data was used for the research described in the article.

## References

[1] X. Renaudin, Reactive oxygen species and DNA damage response in cancer, Int Rev. Cell Mol. Biol. 364 (2021) 139–161, https://doi.org/10.1016/bs.ircmb.2021.04.001.

[2] C.G. Fraga, M.K. Shigenaga, J.W. Park, P. Degan, B.N. Ames, Oxidative damage to DNA during aging: 8-hydroxy-2'-deoxyguanosine in rat organ DNA and urine, Proc. Natl. Acad. Sci. USA 87 (1990) 4533–4537, https://doi.org/10.1073/pnas.87.12.4533.

[3] E. Mullaart, P.H. Lohman, F. Berends, J. Vijg, DNA damage metabolism and aging, Mutat. Res 237 (1990) 189–210, https://doi.org/10.1016/0921-8734(90) 90001-8.

[4] S. Nik-Zainal, H. Davies, J. Staaf, M. Ramakrishna, D. Glodzik, X. Zou, I. Martincorena, L.B. Alexandrov, S. Martin, D.C. Wedge, P. Van Loo, Y.S. Ju, M. Smid, A.B. Brinkman, S. Morganella, M.R. Aure, O.C. Lingjærde, A. Langerod, M. Ringnér, S.-M. Ahn, S. Boyault, J.E. Brock, A. Broeks, A. Butler, C. Desmedt, L. Dirix, S. Dronov, A. Fatima, J.A. Foekens, M. Gerstung, G.K.J. Hooijer, S. J. Jang, D.R. Jones, H.-Y. Kim, T.A. King, S. Krishnamurthy, H.J. Lee, J.-Y. Lee, Y. Li, S. McLaren, A. Menzies, V. Mustonen, S. O'Meara, I. Pauporté, X. Pivot, C. A. Purdie, K. Raine, K. Ramakrishnan, F.G. Rodríguez-González, G. Romieu, A. M. Sieuwerts, P.T. Simpson, R. Shepherd, L. Stebbings, O.A. Stefansson, J. Teague, S. Tommasi, I. Treilleux, G.G. Van den Eynden, P. Vermeulen, A. Vincent-Salomon, L. Yates, C. Caldas, L. van't Veer, A. Tutt, S. Knappskog, B.K. T. Tan, J. Jonkers, Á. Borg, N.T. Ueno, C. Sotiriou, A. Viari, P.A. Futreal, P. J. Campbell, P.N. Span, S. Van Laere, S.R. Lakhani, J.E. Eyfjord, A.M. Thompson, E. Birney, H.G. Sunnenberg, M.J. van de Vijver, J.W.M. Martens, A.-L. Borresen-Dale, A.L. Richardson, G. Kong, G. Thomas, M.R. Stratton, Landscape of somatic mutations in 560 breast cancer whole-genome sequences, Nature 534 (2016) 47–54, https://doi.org/10.1038/nature17676.

[5] X. Zou, M. Owusu, R. Harris, S.P. Jackson, J.I. Loizou, S. Nik-Zainal, Validating the concept of mutational signatures with isogenic cell models, Nat. Commun. 9 (2018) 1744, https://doi.org/10.1038/s41467-018-04052-8.

[6] C. Cordero, K.P.M. Mehta, T.M. Weaver, J.A. Ling, B.D. Freudenthal, D. Cortez, S. A. Roberts, Contributing factors to the oxidation-induced mutational landscape in human cells, Nat. Commun. 15 (2024) 10722, https://doi.org/10.1038/s41467-024-55497-z.

[7] G.L. Dianov, U. Hübscher, Mammalian Base Excision Repair: the Forgotten Archangel, Nucleic Acids Res. 41 (2013) 3483–3490, https://doi.org/10.1093/nar/gkt076.

[8] K.K.L. Chan, Q.-M. Zhang, G.L. Dianov, Base excision repair fidelity in normal and cancer cells, Mutagenesis 21 (2006) 173–178, https://doi.org/10.1093/mutage/gel020.

[9] M. García-Díaz, K. Bebenek, R. Sabariegos, O. Domínguez, J. Rodríguez, T. Kirchhoff, E. García-Palomero, A.J. Picher, R. Juárez, J.F. Ruiz, T.A. Kunkel, L. Blanco, DNA polymerase lambda, a novel DNA repair enzyme in human cells, J. Biol. Chem. 277 (2002) 13184–13191, https://doi.org/10.1074/jbc.M111601200.

[10] S. Boiteux, F. Coste, B. Castaing, Repair of 8-oxo-7,8-dihydroguanine in prokaryotic and eukaryotic cells: properties and biological roles of the Fpg and OGG1 DNA N-glycosylases, Free Radic. Biol. Med 107 (2017) 179–201, https://doi.org/10.1016/j.freeradbiomed.2016.11.042.

[11] D. Lia, A. Reyes, J.T.A. de Melo Campos, T. Piolot, J. Baijer, J.P. Radicella, A. Campalans, Mitochondrial maintenance under oxidative stress depends on mitochondrially localised α-OGG1, J. Cell Sci. 131 (2018) jcs213538, https://doi.org/10.1242/jcs.213538.

[12] N.C. de Souza-Pinto, L. Eide, B.A. Hogue, T. Thybo, T. Stevnsner, E. Seeberg, A. Klungland, V.A. Bohr, Repair of 8-oxodeoxyguanosine lesions in mitochondrial dna depends on the oxoguanine dna glycosylase (OGG1) gene and 8-oxoguanine accumulates in the mitochondrial dna of OGG1-defective mice, Cancer Res 61 (2001) 5378–5381.

[13] K. Nishioka, T. Ohtsubo, H. Oda, T. Fujiwara, D. Kang, K. Sugimachi, Y. Nakabeppu, Expression and differential intracellular localization of two major forms of human 8-oxoguanine DNA glycosylase encoded by alternatively spliced OGG1 mRNAs, Mol. Cell 10 (1999) 1637–1652, https://doi.org/10.1091/mbc.10.5.1637.

[14] Z. Rong, P. Tu, P. Xu, Y. Sun, F. Yu, N. Tu, L. Guo, Y. Yang, The mitochondrial response to DNA damage, Front. Cell Dev. Biol. 9 (2021), https://doi.org/10.3389/fcell.2021.669379.

[15] L. Kazak, A. Reyes, I.J. Holt, Minimizing the damage: repair pathways keep mitochondrial DNA intact, Nat. Rev. Mol. Cell Biol. 13 (2012) 659–671, https://doi.org/10.1038/nrm13439.

[16] J.G. Mabley, P. Pacher, A. Deb, R. Wallace, R.H. Elder, C. Szabó, Potential role for 8-oxoguanine DNA glycosylase in regulating inflammation, FASEB J. 19 (2005) 290–292, https://doi.org/10.1096/fj.04-2278fje.

[17] E. Touati, V. Michel, J.-M. Thiberge, P. Avé, M. Huerre, F. Bourgade, A. Klungland, A. Labigne, Deficiency in OGG1 protects against inflammation and mutagenic effects associated with H. pylori infection in mouse, Helicobacter 11 (2006) 494–505, https://doi.org/10.1111/j.1523-5378.2006.00442.x.

[18] G. Li, K. Yuan, C. Yan, J. Fox, M. Gaid, W. Breitwieser, A.K. Bansal, H. Zeng, H. Gao, M. Wu, 8-Oxoguanine-DNA glycosylase 1 deficiency modifies allergic airway inflammation by regulating STAT6 and IL-4 in cells and in mice, Free Radic. Biol. Med 52 (2012) 392–401, https://doi.org/10.1016/j.freeradbiomed.2011.10.490.

[19] X. Ba, A. Bacsi, J. Luo, L. Aguilera-Aguirre, X. Zeng, Z. Radak, A.R. Brasier, I. Boldogh, 8-oxoguanine DNA glycosylase-1 augments proinflammatory gene expression by facilitating the recruitment of site-specific transcription factors, J. Immunol. 192 (2014) 2384–2394, https://doi.org/10.4049/jimmunol.1302472.

[20] R. Wang, W. Hao, L. Pan, I. Boldogh, X. Ba, The roles of base excision repair enzyme OGG1 in gene expression, Cell Mol. Life Sci. 75 (2018) 3741–3750, https://doi.org/10.1007/s00018-018-2887-8.

[21] A.-M. Di Guilmi, N. Fonknechten, A. Campalans, OGG1 at the crossroads between repair and transcriptional regulation, in: N. Sugimoto (Ed.), Handbook of
Chemical Biology of Nucleic Acids, Springer Nature, Singapore, 2022, pp. 1–34, https://doi.org/10.1007/978-981-16-1313-5-50-1.

[22] F. Hans, M. Senarisoy, C. Bhaskar Naidu, J. Timmins, Focus on DNA glycosylases—a set of tightly regulated enzymes with a high potential as anticancer drug targets, Int. J. Mol. Sci. 21 (2020) 9226, https://doi.org/10.3390/ijms21239226.

[23] G.J. Grundy, J.L. Parsons, Base excision repair and its implications to cancer therapy, Essays Biochem 64 (2020) 831–843, https://doi.org/10.1042/EBC20200013.

[24] H. Farmer, N. McCabe, C.J. Lord, A.N.J. Tutt, D.A. Johnson, T.B. Richardson, M. Santarosa, K.J. Dillon, I. Hickson, C. Knights, N.M.B. Martin, S.P. Jackson, G.C. M. Smith, A. Ashworth, Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy, Nature 434 (2005) 917–921, https://doi.org/10.1038/nature03445.

[25] P.C. Fong, D.S. Boss, T.A. Yap, A. Tutt, P. Wu, M. Mergui-Roelvink, P. Mortimer, H. Swaisland, A. Lau, M.J. O'Connor, A. Ashworth, J. Carmichael, S.B. Kaye, J.H. M. Schellens, J.S. de Bono, Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers, N. Engl. J. Med 361 (2009) 123–134, https://doi.org/10.1056/NEJMoa0900212.

[26] M. Robson, S.-A. Im, E. Senkus, B. Xu, S.M. Domchek, N. Masuda, S. Delaloge, W. Li, N. Tung, A. Armstrong, W. Wu, C. Goessl, S. Runswick, P. Conte, Olaparib for metastatic breast cancer in patients with a germline BRCA mutation, N. Engl. J. Med 377 (2017) 523–533, https://doi.org/10.1056/NEJMoa1706450.

[27] J.M. Baquero, E. Marchena-Perea, R. Mirabet, R. Torres-Ruiz, C. Blanco-Aparicio, S. Rodríguez-Perales, T. Helleday, C. Benítez, A. Osorio, OGG1 inhibition triggers synthetic lethality and enhances the effect of PARP inhibitor olaparib in BRCA1-deficient TNBC cells, Front Oncol. 12 (2022) 888810, https://doi.org/10.3389/fonc.2022.888810.

[28] N. Chopra, H. Tovey, A. Pearson, R. Cutts, C. Toms, P. Proszek, M. Hubank, M. Dowsett, A. Dodson, F. Daley, D. Kriplani, H. Gevensleben, H.R. Davies, A. Degasperi, R. Roylance, S. Chan, A. Tutt, A. Skene, A. Evans, J.M. Bliss, S. Nik-Zainal, N.C. Turner, Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer, Nat. Commun. 11 (2020) 2662, https://doi.org/10.1038/s41467-020-16142-7.

[29] S.M. Noordermeer, H. van Attikum, PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells, Trends Cell Biol. 29 (2019) 820–834, https://doi.org/10.1016/j.tcb.2019.07.008.

[30] T. Visnes, C. Benítez-Buelga, A. Cázares-Körner, K. Sanjiv, B.M.F. Hanna, O. Mortusewicz, V. Rajagopal, J.J. Albers, D.W. Hagey, T. Calderón, S. Rodriguez-Perales, J. Benítez, H.E. Krokan, A. Altun, P. Stenmark, U.W. Berglund, T. Helleday, Targeting OGG1 arrests cancer cell proliferation by inducing replication stress, Nucleic Acids Res 48 (2020) 12234–12251, https://doi.org/10.1093/nar/gkaa1048.

[31] M.R. Fabbrizi, C.M. Nickson, J.R. Hughes, E.A. Robinson, K. Vaidya, C.P. Rubbi, A. Kacperek, H.E. Bryant, T. Helleday, J.L. Parsons, Targeting OGG1 and PARG radiosensitises head and neck cancer cells to high-LET protons through complex DNA damage persistence, Cell Death Dis. 15 (2024) 1–11, https://doi.org/10.1038/s41419-024-06541-9.

[32] I. Morland, L. Luna, E. Gustad, E. Seeberg, M. Bjørås, Product inhibition and magnesium modulate the dual reaction mode of hggp1, DNA Repair (Amst.) 4 (2005) 381–387, https://doi.org/10.1016/j.dnarep.2004.11.002.

[33] N. Donley, P. Jaruga, E. Coskun, M. Dizdaroglu, A.K. McCullough, R.S. Lloyd, Small molecule inhibitors of 8-oxoguanine DNA glycosylase-1 (OGG1), ACS Chem. Biol. 10 (2015) 2334–2343, https://doi.org/10.1021/acscchembio.5b00452.

[34] O. D'Augustin, V. Gaudon, C. Siberchicot, R. Smith, C. Chapuis, J. Depagne, X. Veaute, D. Busso, A.-M. Di Guilmi, B. Castaing, J.P. Radicella, A. Campalans, S. Huet, Identification of key residues of the DNA glycosylase OGG1 controlling efficient DNA sampling and recruitment of oxidized bases in living cells, Nucleic Acids Res 51 (2023) 4942–4958, https://doi.org/10.1093/nar/ggd243.

[35] Y.-K. Tahara, D. Auld, D. Ji, A.A. Beharry, A.M. Kietrys, D.L. Wilson, M. Jimenez, D. King, Z. Nguyen, E.T. Kool, Potent and selective inhibitors of 8-oxoguanine DNA glycosylase, J. Am. Chem. Soc. 140 (2018) 2105–2114, https://doi.org/10.1021/jacs.7b09316.

[36] T. Visnes, A. Cázares-Körner, W. Hao, O. Wallner, G. Masuyer, O. Loseva, O. Mortusewicz, E. Wiita, A. Sarno, A. Manoilov, J. Astorga-Wells, A.-S. Jemth, L. Pan, K. Sanjiv, S. Karsten, C. Gokturk, M. Grube, E.J. Homan, B.M.F. Hanna, C. B.J. Paulin, T. Pham, A. Rasti, U.W. Berglund, C. von Nicolai, C. Benitez-Buelga, T. Koolmeister, D. Ivanic, P. Iliev, M. Scobie, H.E. Krokan, P. Baranczewski, P. Artursson, M. Altun, A.J. Jensen, C. Kalderén, X. Ba, R.A. Zubarev, P. Stenmark, I. Boldogh, T. Helleday, Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation, Science 362 (2018) 834–839, https://doi.org/10.1126/science.aar0848.

[37] B.M.F. Hanna, T. Helleday, O. Mortusewicz, OGG1 inhibitor TH5487 alters OGG1 chromatin dynamics and prevents incisions, Biomolecules 10 (2020) 1483, https://doi.org/10.3390/biom10111483.

[38] O. Wallner, A. Cázares-Körner, E.R. Scaletti, G. Masuyer, T. Bekkhus, T. Visnes, K. Mamonov, F. Ortiz, T. Lundbäck, M. Volkova, T. Koolmeister, E. Wiita, O. Loseva, M. Pandey, E. Homan, C. Davies, M. Scobie, U. Warpsman Berglund, C. Kalderén, P. Stenmark, T. Helleday, M. Michel, Optimization of N-piperidinyl-benzimidazolone derivatives as potent and

selective inhibitors of 8-oxo-guanine DNA glycosylase 1, ChemMedChem 18 (2023) e202200310, https://doi.org/10.1002/cmdc.202200310.

[39] J.M. Baquero, C. Benítez-Buelga, V. Rajagopal, Z. Zhenjun, R. Torres-Ruiz, S. Müller, B.M.F. Hanna, O. Loseva, O. Wallner, M. Michel, S. Rodríguez-Perales, H. Gad, T. Visnes, T. Helleday, J. Benítez, A. Osorio, Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects, Sci. Rep. 11 (2021) 3490, https://doi.org/10.1038/s41598-021-82917-7.

[40] R. Wang, C. Li, P. Qiao, Y. Xue, X. Zheng, H. Chen, X. Zeng, W. Liu, I. Boldogh, X. Ba, OGG1-initiated base excision repair exacerbates oxidative stress-induced parthanatos, Cell Death Dis. 9 (2018) 628, https://doi.org/10.1038/s41419-018-0680-0.

[41] S. Giovannini, M.-C. Weller, S. Repmann, H. Moch, J. Jiricny, Synthetic lethality between BRCA1 deficiency and poly(ADP-ribose) polymerase inhibition is modulated by processing of endogenous oxidative DNA damage, Nucleic Acids Res 47 (2019) 9132–9143, https://doi.org/10.1093/nar/gkz624.

[42] A. Samaila, R. Basir, M. Gambo Lawal, R. Abas, M.A. Abdullah, R. Abd Majid, N. Nordin, M.K. Hussain, N.I. Ab Razak, Y. Yoke Keong, B. Aliyu, Targeting 8-oxoguanine DNA glycosylase-1 (OGG1) as a therapeutic strategy in inflammatory-related diseases, Immunopharmacol. Immunotoxicol. 46 (2024) 685–694, https://doi.org/10.1080/08923973.2024.2391471.

[43] Y. Zhong, X. Zhang, R. Feng, Y. Fan, Z. Zhang, Q.-W. Zhang, J.-B. Wan, Y. Wang, H. Yu, G. Li, OGG1: an emerging multifunctional therapeutic target for the treatment of diseases caused by oxidative DNA damage, Med Res Rev. (2024), https://doi.org/10.1002/med.22068.

[44] A.M. Fleming, C.J. Burrows, Oxidative stress-mediated epigenetic regulation by G-quadruplexes, NAR Cancer 3 (2021) zcab038, https://doi.org/10.1093/narcan/zcab038.

[45] W. Hao, J. Wang, Y. Zhang, C. Wang, L. Xia, W. Zhang, M. Zafar, J.-Y. Kang, R. Wang, A. Ali Bohio, L. Pan, X. Zeng, M. Wei, I. Boldogh, X. Ba, Enzymatically inactive OGG1 binds to DNA and steers base excision repair toward gene transcription, FASEB J. 34 (2020) 7427–7441, https://doi.org/10.1096/fj.201902243R.

[46] A. Bravard, M. Vacher, B. Gouget, A. Cautant, F.H. de Boisferon, S. Marsin, S. Chevillard, J.P. Radicella, Redox regulation of human OGG1 activity in response to cellular oxidative stress, Mol. Cell Biol. 26 (2006) 7430–7436, https://doi.org/10.1128/MCB.00624-06.

[47] X. Zheng, K. Wang, L. Pan, W. Hao, Y. Xue, A. Baci, S.A. Vlahopoulos, Z. Radak, T.K. Hazra, A.R. Basier, L. Tanner, X. Ba, I. Boldogh, Innate immune responses to RSV infection facilitated by OGG1, an enzyme repairing oxidatively modified DNA base lesions, J. Innate Immun. 14 (2022) 593–614, https://doi.org/10.1159/000524186.

[48] L. Pan, W. Hao, Y. Xue, K. Wang, X. Zheng, J. Luo, X. Ba, Y. Xiang, X. Qin, J. Bergwik, L. Tanner, A. Egesten, A.R. Basier, I. Boldogh, 8-Oxoguanine targeted by 8-oxoguanine DNA glycosylase 1 (OGG1) is central to fibrogenic gene activation upon lung injury, Nucleic Acids Res 51 (2023) 1087–1102, https://doi.org/10.1093/nar/gka1241.

[49] K. Le, Z. Quezado, H. Li, S. Kamimura, M.L. Smith, Y. Tahara, Y. Lee, A. Conrey, J. Schultz, T. Andresson, E.T. Kool, S.L. Thein, 8-oxoguanine DNA glycosylase 1 recruits transcription factor STAT1 to promote the inflammatory responses in sickle cell disease, Blood 144 (2024) 2490, https://doi.org/10.1182/blood-2024-201619.

[50] A.R. Collins, J. Cadet, L. Möller, H.E. Poulsen, J. Viña, Are we sure we know how to measure 8-oxo-7,8-dihydroguanine in DNA from human cells? Arch. Biochem. Biophys. 423 (2004) 57–65, https://doi.org/10.1016/j.abb.2003.12.022.

[51] R. Amouroux, A. Campalans, B. Epe, J.P. Radicella, Oxidative stress triggers the preferential assembly of base excision repair complexes on open chromatin regions, Nucleic Acids Res 38 (2010) 2878–2890, https://doi.org/10.1093/nar/gkp1247.

[52] D.W. Clark, T. Phang, M.G. Edwards, M.W. Geraci, M.N. Gillespie, Promoter G-quadruplex sequences are targets for base oxidation and strand cleavage during hypoxia-induced transcription, Free Radic. Biol. Med. 53 (2012) 51–59, https://doi.org/10.1016/j.freeradbiomed.2012.04.024.

[53] Y. Ding, A.M. Fleming, C.J. Burrows, Sequencing the mouse genome for the oxidatively modified base 8-Oxo-7,8-dihydroguanine by OG-Seq, J. Am. Chem. Soc. 139 (2017) 2569–2572, https://doi.org/10.1021/jacs.6b12604.

[54] Y. Fang, P. Zou, Genome-wide mapping of oxidative DNA damage via engineering of 8-oxoguanine DNA glycosylase, Biochemistry 59 (2020) 85–89, https://doi.org/10.1021/acs.biochem.9b00782.

[55] A.M. Fleming, Y. Ding, C.J. Burrows, Oxidative DNA damage is epigenetic by regulating gene transcription via base excision repair, Proc. Natl. Acad. Sci. 114 (2017) 2604–2609, https://doi.org/10.1073/pnas.1619809111.

[56] J. Allgayer, N. Kitsera, S. Bartelt, B. Epe, A. Khobta, Widespread transcriptional gene inactivation initiated by a repair intermediate of 8-oxoguanine, Nucleic Acids Res 44 (2016) 7267–7280, https://doi.org/10.1093/nar/gkw473.

[57] T. Obermann, T. Sakshaug, V.V. Kanagaraj, A. Abentung, M.M.L. de Sousa, L. Hagen, A. Sarno, M. Bjørås, K. Scheffler, Genomic 8-oxoguanine modulates gene transcription independent of its repair by DNA glycosylases OGG1 and MUTYH, Redox Biol. 79 (2025) 103461, https://doi.org/10.1016/j.redox.2024.103461.

[58] U.K. Shigdel, V. Ovchinnikov, S.-J. Lee, J.A. Shih, M. Karplus, K. Nam, G. L. Verdine, The trajectory of intrahelical lesion recognition and extrusion by the human 8-oxoguanine DNA glycosylase, Nat. Commun. 11 (2020) 4437, https://doi.org/10.1038/s41467-020-18290-2.
[59] Q. You, X. Feng, Y. Cai, S.B. Baylin, H. Li, Human 8-oxoguanine glycosylase OGG1 binds nucleosome at the dsDNA ends and the super-helical locations, Commun. Biol. 7 (2024) 1–12, https://doi.org/10.1038/s42003-024-06917.

[60] H. Menoni, D. Gasparutto, A. Hamiche, J. Cadet, S. Dimitrov, P. Bouvet, D. Angelov, ATP-dependent chromatin remodeling is required for base excision repair in conventional but not in variant H2A.Bbd nucleosomes, Mol. Cell Biol. 27 (2007) 5949–5956, https://doi.org/10.1128/MCB.03767-07.

[61] E. Lebraud, G. Pinna, C. Siberchicot, J. Depagne, D. Busso, D. Fantini, L. Irbah, E. Robeska, G. Kratassiouk, J.-L. Ravanat, B. Epe, J.P. Radicella, A. Campalans, Chromatin recruitment of OGG1 requires cohesin and mediator and is essential for efficient 8-oxoG removal, Nucleic Acids Res 48 (2020) 9082–9097, https://doi.org/10.1093/nar/gka611.

[62] J.A. Marteijn, H. Lans, W. Vermeulen, H.J.H. Hoeijmakers, Understanding nucleotide excision repair and its roles in cancer and ageing, Nat. Rev. Mol. Cell Biol. 15 (2014) 465–481, https://doi.org/10.1038/nrm3822.

[63] S. Jang, N. Kumar, E.C. Beckwitt, M. Kong, E. Fouquerel, V. Rapić-Otrin, R. Prasad, S.C. Watkins, C. Khuu, C. Majumdar, S.S. David, S.H. Wilson, M. P. Bruchez, P.L. Opresko, B. Van Houten, Damage sensor role of UV-DDB during base excision repair, Nat. Struct. Mol. Biol. 26 (2019) 695–703, https://doi.org/10.1038/s41594-019-0261-7.

[64] N. Kumar, A.F. Theil, V. Roginskaya, Y. Ali, M. Calderon, S.C. Watkins, P. Barnes, P.L. Opresko, A. Pines, H. Lans, W. Vermeulen, B. Van Houten, Global and transcription-coupled repair of 8-oxoG is initiated by nucleotide excision repair proteins, Nat. Commun. 13 (2022) 974, https://doi.org/10.1038/s41467-022-28642-9.

[65] M.A. Schaich, B.L. Schnable, N. Kumar, V. Roginskaya, R.C. Jakielski, R. Urban, Z. Zhong, N.M. Kad, B. Van Houten, Single-molecule analysis of DNA-binding proteins from nuclear extracts (SMADNE), Nucleic Acids Res 51 (2023) e39, https://doi.org/10.1093/nar/gkad095.

[66] E. Fouquerel, R.P. Barnes, S. Uttam, S.C. Watkins, M.P. Bruchez, P.L. Opresko, Targeted and persistent 8-oxoguanine base damage at telomeres promotes telomere loss and crisis, Mol. Cell 75 (2019) 117–130.e6, https://doi.org/10.1016/j.molcel.2019.04.024.

[67] A. Lin, C.J. Giuliano, A. Palladino, K.M. John, C. Abramowicz, M.L. Yuan, E. L. Sausville, D.A. Lukow, L. Liu, A.R. Chait, Z.C. Galluzzo, C. Tucker, J. M. Sheltzer, Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials, Sci. Transl. Med. 11 (2019) eaaw8412, https://doi.org/10.1126/scitranslmed.aaw8412.

[68] D. Sun, W. Gao, H. Hu, S. Zhou, Why 90% of clinical drug development fails and how to improve it? Acta Pharm. Sin. B 12 (2022) 3049–3062, https://doi.org/10.1016/j.apsb.2022.02.002.

[69] X. Tanushi, G. Pinna, M. Vandamme, C. Siberchicot, O. D'Augustin, A.-M. Di Guilmi, J.P. Radicella, B. Castaing, R. Smith, S. Huet, F. Leteurtre, A. Campalans, OGG1 competitive inhibitors show important off-target effects by directly inhibiting efflux pumps and disturbing mitotic progression, Front Cell Dev. Biol. 11 (2023) 1124960, https://doi.org/10.3389/fcell.2023.1124960.

[70] J.I. Fletcher, M. Haber, M.J. Henderson, M.D. Norris, ABC transporters in cancer: more than just drug efflux pumps, Nat. Rev. Cancer 10 (2010) 147–156, https://doi.org/10.1038/nrc2789.

[71] J.-Q. Wang, Z.-X. Wu, Y. Yang, Q.-X. Teng, Y.-D. Li, Z.-N. Lei, K.A. Jani, N. Kaushal, Z.-S. Chen, ATP-binding cassette (ABC) transporters in cancer: A review of recent updates, J. Evid. Based Med. Rev. 14 (2021) 232–256, https://doi.org/10.1111/jebm.12434.

[72] S.G. Rudd, H. Gad, K. Sanjiv, N. Amaral, A. Hagenkort, P. Groth, C.E. Ström, O. Mortusewicz, U.W. Berglund, T. Helleday, MTH1 inhibitor TH588 disturbs mitotic progression and induces mitosis-dependent accumulation of genomic 8-oxodG, Cancer Res 80 (2020) 3530–3541, https://doi.org/10.1158/0008-5472.CAN-19-0883.

[73] H. Gad, T. Koolmeister, A.-S. Jemth, S. Eshtad, S.A. Jacques, C.E. Ström, L. M. Svensson, N. Schultz, T. Lundbäck, B.O. Einarsdottir, A. Saleh, C. Göktürk, P. Baranczewski, R. Svensson, R.P.-A. Berntsson, R. Gustafsson, C. Strömberg, K. Sanjiv, M.-C. Jacques-Cordonnier, M. Desroses, A.-L. Gustavsson, R. Olofsson, F. Johansson, E.J. Homan, O. Loseva, L. Bräutigam, L. Johansson, A. Höglund, A. Hagenkort, T. Pham, M. Altun, F.Z. Gagauz, S. Vikingsson, B. Evers, M. Henriksson, K.S.A. Vallin, O.A. Wallner, L.G.J. Hammarström, E. Wiita, I. Almlöf, C. Kalderén, H. Axelsson, T. Djureinovic, J.C. Puigvert, M. Häggblad, F. Jeppsson, U. Martens, C. Lundin, B. Lundgren, I. Granelli, A.J. Jensen, M. Artursson, J.A. Nilsson, P. Stenmark, M. Scobie, U.W. Berglund, T. Helleday, MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool, Nature 508 (2014) 215–221, https://doi.org/10.1038/nature13181.

[74] Y.-K. Tahara, A.M. Kietrys, M. Hebenrock, Y. Lee, D.L. Wilson, E.T. Kool, Dual Inhibitors of 8-Oxoguanine Surveillance by OGG1 and NUDT1, ACS Chem. Biol. 14 (2019) 2606–2615, https://doi.org/10.1021/acschembio.9b00490.

[75] M.L. Michaels, J.H. Miller, The GO system protects organisms from the mutagenic effect of the spontaneous lesion 8-hydroxyguanine (7,8-dihydro-8-oxoguanine), J. Bacteriol. 174 (1992) 6321–6325, https://doi.org/10.1128/jb.174.20.6321-6325.1992.

[76] A.V. Endutkin, D.O. Zharkov, GO system, a DNA repair pathway to cope with oxidative damage, Mol. Biol. 55 (2021) 193–210, https://doi.org/10.1134/S0026893321020072.

[77] L. Zhang, L. Misira, G.J. Samaraynake, N. Sharma, D.M. Nguyen, Y.-K. Tahara, E.T. Kool, P. Rai, OGG1 co-inhibition antagonizes the tumor-inhibitory effects of targeting MTH1, Redox Biol. 40 (2021) 101848, https://doi.org/10.1016/j.redox.2020.101848.

[78] K.V.M. Huber, E. Salah, B. Radic, M. Gridling, J.M. Elkins, A. Stukalov, A.-S. Jemth, C. Göktürk, K. Sanjiv, K. Strömberg, T. Pham, U.W. Berglund, J. Colinge, K.L. Bennett, J.I. Loizou, T. Helleday, S. Knapp, G. Superti-Furga, Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy, Nature 508 (2014) 222–227, https://doi.org/10.1038/nature13194.

[79] J.G. Kettle, H. Alwan, M. Bista, J. Breed, N.L. Davies, K. Eckersley, S. Filery, K. M. Foote, L. Goodwin, D.R. Jones, H. Käck, A. Lau, J.W.M. Nissink, J. Read, J. S. Scott, B. Taylor, G. Walker, L. Wissler, M. Wylot, Potent and selective inhibitors of MTH1 probe its role in cancer cell survival, J. Med Chem. 59 (2016) 2346–2361, https://doi.org/10.1021/acs.jmedchem.5b01760.

[80] P. Petrocchi, E. Leo, N.J. Reyna, M.M. Hamilton, X. Shi, C.A. Parker, F. Mseej, H. P. Bardenhagen, P. Leonard, J.B. Cross, S. Huang, Y. Jiang, M. Cardozo, G. Draetta, J.R. Marszalek, C. Toniatti, P. Jones, R.T. Lewis, Identification of potent and selective MTH1 inhibitors, Bioorg. Med. Chem. Lett. 26 (2016) 1503–1507, https://doi.org/10.1016/j.bmcl.2016.02.026.

[81] T. Kawamura, M. Kawatani, M. Muroi, Y. Kondoh, Y. Futamura, H. Aono, M. Tanaka, K. Honda, H. Osada, Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival, Sci. Rep. 6 (2016) 26521, https://doi.org/10.1038/srep26521.

[82] A. Taiyab, A. Ashraf, M.N. Sulaimani, A. Rathi, A. Shamsi, M.I. Hassan, Role of MTH1 in oxidative stress and therapeutic targeting of cancer, Redox Biol. 77 (2024) 103394, https://doi.org/10.1016/j.redox.2024.103394.

[83] G. Sharbeen, J. Youkhana, A. Mawson, J. McCarroll, A. Nunez, A. Biankin, A. Johns, D. Goldstein, P. Phillips, MutY-Homolog (MYH) inhibition reduces pancreatic cancer cell growth and increases chemosensitivity, Oncotarget 8 (2017) 9216–9229, https://doi.org/10.18632/oncotarget.13985.

[84] M.D. Rosa, R.P. Barnes, P.R. Nyalapatla, P. Wipf, P.L. Opresko, OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced cellular senescence, (2023) 2023.04.10.536247, https://doi.org/10.1101/2023.04.10.536247.

[85] B.A. Baptiste, S.R. Katchur, E.M. Fivenson, D.L. Croteau, W.L. Rumsey, V.A. Bohr, Enhanced mitochondrial DNA repair of the common disease-associated variant, Ser326Cys, of hOGG1 through small molecule intervention, Free Radic. Biol. Med 124 (2018) 149–162, https://doi.org/10.1016/j.freeradbiomed.2018.05.094.

[86] M. Michel, C. Benítez-Buelga, P.A. Calvo, B.M.F. Hanna, O. Mortusewicz, G. Masuyer, J. Davies, O. Wallner, K. Sanjiv, J.J. Albers, S. Castaneda-Zegarra, A.-S. Jemth, T. Visnes, A. Sastre-Perona, A.N. Danda, E.J. Homan, K. Marimuthu, Z. Zhenjun, C.N. Chi, A. Sarno, E. Wiita, C. von Nicolai, A.J. Komor, V. Rajagopal, S. Müller, E.C. Hank, M. Varga, E.R. Scaletti, M. Pandey, S. Karsten, H. Haslen-Hox, S. Loevenich, P. Marttila, A. Rasti, K. Mamonov, F. Ortis, F. Schömmberg, O. Loseva, J. Stewart, N. D'Arcy-Evans, T. Koolmeister, M. Henriksson, D. Michel, A. de Ory, L. Acero, O. Calvete, M. Scobie, C. Hertweck, I. Vilotijevic, C. Kalderén, A. Osorio, R. Perona, A. Stolz, P. Stenmark, U.W. Berglund, M. de Vega, T. Helleday, Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function, Science 376 (2022) 1471–1476, https://doi.org/10.1126/science.abf8980.

[87] S.S.B. Komakula, J. Tumova, D. Kumaraswamy, N. Burchat, V. Vartanian, H. Ye, A. Dobrzn, R.S. Lloyd, H. Sampath, The DNA repair protein OGG1 protects against obesity by altering mitochondrial energetics in white adipose tissue, Sci. Rep. 8 (2018) 14886, https://doi.org/10.1038/s41598-018-33511-1.

[88] S. Oka, J. Leon, K. Sakumi, N. Abolhassani, Z. Sheng, D. Tschimoto, F. M. LaFerla, Y. Nakabeppu, MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis, Sci. Rep. 11 (2021) 5819, https://doi.org/10.1038/s41598-021-8460-9.

[89] C. Benítez-Buelga, T. Helleday, M. Michel, Synthetic switches of OGG1 control initiation of base excision repair and offer new treatment strategies, Clin. Transl. Med 12 (2022) e1035, https://doi.org/10.1002/cntm.21035.

[90] G. Tian, S.R. Katchur, Y. Jiang, J. Briand, M. Schaber, C. Kreatsoulas, B. Schwartz, S. Thrall, A.M. Davis, S. Duvall, B.A. Kaufman, W.L. Rumsey, Small molecule-mediated allosteric activation of the base excision repair enzyme 8-oxoguanine DNA glycosylase and its impact on mitochondrial function, Sci. Rep. 12 (2022) 14685, https://doi.org/10.1038/s41598-022-18878-2.

[91] A.W. Dobson, Y. Xu, M.R. Kelley, S.P. LeDoux, G.L. Wilson, Enhanced mitochondrial DNA repair and cellular survival after oxidative stress by targeting the human 8-oxoguanine glycosylase repair enzyme to mitochondria, J. Biol. Chem. 275 (2000) 37518–37523, https://doi.org/10.1074/jbc.M000831200.

[92] L.I. Rachek, V.I. Grishko, S.I. Musiyenko, M.R. Kelley, S.P. LeDoux, G.L. Wilson, Conditional targeting of the DNA repair enzyme hOGG1 into mitochondria, J. Biol. Chem. 277 (2002) 44932–44937, https://doi.org/10.1074/jbc.M208777020.

[93] Y. Cheng, X. Ren, A.S.P. Gowda, Y. Shan, L. Zhang, Y.-S. Yuan, R. Patel, H. Wu, K. Huber-Keener, J.W. Yang, D. Liu, T.E. Spratt, J.-M. Yang, Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress, Cell Dis. 4 (2013) e731, https://doi.org/10.1038/cddis.2013.254.

[94] J.H.K. Kauppila, N.A. Bonekamp, A. Mourier, M.A. Isokallio, A. Just, T.E. S. Kauppila, J.B. Stewart, N.-G. Larsson, Base-excision repair deficiency alone or combined with increased oxidative stress does not increase mtDNA point mutations in mice, Nucleic Acids Res 46 (2018) 6642–6669, https://doi.org/10.1038/nar/gky456.

[95] A.P. West, W. Khoury-Hanold, M. Staron, M.C. Tal, C.M. Pineda, S.M. Lang, M. Bestwick, B.A. Dugway, N. Raimundo, D.A. MacDuff, S.M. Kaech, J.R. Smiley, R.E. Means, A. Iwasaki, G.S. Shadel, Mitochondrial DNA stress primes the antiviral innate immune response, Nature 520 (2015) 553–557, https://doi.org/10.1038/nature14156.

[96] Z. Wu, S. Oeck, A.P. West, K.C. Mangalhara, A.G. Sainz, L.E. Newman, X.-O. Zhang, L. Wu, Q. Yan, M. Bosenberg, Y. Liu, P.L. Sulkowski, V. Tripple, S.
M. Kaech, P.M. Glazer, G.S. Shadel, Mitochondrial DNA stress signalling protects the nuclear genome, Nat. Metab. 1 (2019) 1209–1218, https://doi.org/10.1038/s42255-019-0150-8.

[97] Z. Wu, A.G. Sainz, G.S. Shadel, Mitochondrial DNA: cellular genotoxic stress sentinel, Trends Biochem Sci. 46 (2021) 812–821, https://doi.org/10.1016/j.tibs.2021.05.004.

[98] H. Xian, K. Watari, E. Sanchez-Lopez, J. Offenberger, J. Onyuru, H. Sampath, W. Ying, H.M. Hoffman, G.S. Shadel, M. Karin, Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling, Immunity 55 (2022) 1370–1385.e8, https://doi.org/10.1016/j.immuni.2022.06.007.

[99] R.R. Weichselbaum, H. Ishwaran, T. Yoon, D.S.A. Nuyten, S.W. Baker, N. Khodarev, A.W. Su, A.Y. Shaikh, P. Roach, B. Kreike, B. Roizman, J. Bergh, Y. Pawitan, M.J. van de Vijver, A.J. Minn, An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer, Proc. Natl. Acad. Sci. USA 105 (2008) 18490–18495, https://doi.org/10.1073/pnas.0809242105.

[100] M. Hussain, X. Chu, B. Duan Sahbaz, S. Gray, K. Pekhale, J.-H. Park, D.L. Croteau, V.A. Bohr, Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA, Free Radic. Biol. Med 203 (2023) 34–44, https://doi.org/10.1016/j.freeradbiomed.2023.03.262.

[101] H. Xian, M. Karin, Oxidized mitochondrial DNA: a protective signal gone awry, Trends Immunol. 44 (2023) 188–200, https://doi.org/10.1016/j.it.2023.01.006.

[102] Z. Zhong, S. Liang, E. Sanchez-Lopez, F. He, S. Shalapour, X.-J. Lin, J. Wong, S. Ding, E. Seki, B. Schnabl, A.L. Hevener, H.B. Greenberg, T. Kisseleva, M. Karin, New mitochondrial DNA synthesis enables NLRP3 inflammasome activation, Nature 560 (2018) 198–203, https://doi.org/10.1038/s41586-018-0372-z.

[103] W. Zhang, D. Xiao, Q. Mao, H. Xia, Role of neuroinflammation in neurodegeneration development, Sig Transduct. Target Ther. 8 (2023) 1–32, https://doi.org/10.1038/s41392-023-01486-5.

[104] B. Szczesny, T.K. Hazra, J. Papaconstantinou, S. Mitra, I. Boldogh, Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of

oxidatively damaged bases, Proc. Natl. Acad. Sci. USA 100 (2003) 10670–10675, https://doi.org/10.1073/pnas.1932854100.

[105] K.A. Conlon, M. Berrios, Site-directed photoproteolysis of 8-oxoguanine DNA glycosylase 1 (OGG1) by specific porphyrin-protein probe conjugates: a strategy to improve the effectiveness of photodynamic therapy for cancer, J. Photochem. Photobio. B 87 (2007) 9–17, https://doi.org/10.1016/j.jphotobiol.2006.12.004.

[106] L. Zhao, J. Zhao, K. Zhong, A. Tong, D. Jia, Targeted protein degradation: mechanisms, strategies and application, Sig Transduct. Target Ther. 7 (2022) 1–13, https://doi.org/10.1038/s41392-022-00966-4.

[107] X. Lin, H. Xiang, G. Luo, Targeting estrogen receptor α for degradation with PROTACs: A promising approach to overcome endocrine resistance, Eur. J. Med Chem. 206 (2020) 112689, https://doi.org/10.1016/j.ejmech.2020.112689.

[108] L. Bai, H. Zhou, R. Xu, Y. Zhao, K. Chinnaswamy, D. McEachern, J. Chen, C.-Y. Yang, Z. Liu, M. Wang, L. Liu, H. Jiang, B. Wen, P. Kumar, J.L. Meagher, D. Sun, J.A. Stuckey, S. Wang, A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo, Cancer Cell 36 (2019) 498–511.e17, https://doi.org/10.1016/j.ccell.2019.10.002.

[109] A. Mullard, Targeted protein degraders crowd into the clinic, Nat. Rev. Drug Discov. 20 (2021) 247–250, https://doi.org/10.1038/d41573-021-00052-4.

[110] M. Lauwereys, M. Arbabi Ghahroudi, A. Desmyter, J. Kinne, W. Hölzer, E. De Genst, L. Wyns, S. Muyldermans, Potent enzyme inhibitors derived from dromedary heavy-chain antibodies, EMBO J. 17 (1998) 3512–3520, https://doi.org/10.1093/emboj/17.13.3512.

[111] B.-K. Jin, S. Odongo, M. Radwanska, S. Magez, NANOBODIES®: a review of diagnostic and therapeutic applications, Int J. Mol. Sci. 24 (2023) 5994, https://doi.org/10.3390/ijms24065994.

[112] I. Jovčevska, S. Muyldermans, The therapeutic potential of nanobodies, BioDrugs 34 (2020) 11–26, https://doi.org/10.1007/s40259-019-00392-z.

[113] T. Briolay, T. Petithomme, M. Fouet, N. Nguyen-Pham, C. Blanquart, N. Boisgerault, Delivery of cancer therapies by synthetic and bio-inspired nanovectors, Mol. Cancer 20 (2021) 55, https://doi.org/10.1186/s12943-021-01346-2.