# Ribosome biogenesis and homeostasis: in the front line to cope with cellular stress

Emilie L Cerezo, Yves Henry, Anthony K Henras, Yves Romeo

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Emilie L Cerezo, Yves Henry, Anthony K Henras, Yves Romeo. Ribosome biogenesis and homeostasis: in the front line to cope with cellular stress. Biochimie, 2025, 238 (Pt A), pp.43-56. 10.1016/j.biochi.2025.08.016. hal-05534690

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Submitted on 3 Mar 2026

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<table><tbody><tr><td>3.</td><td>Signaling pathways regulating ribosome biogenesis under stress conditions</td><td>49</td></tr><tr><td>3.1.</td><td>SAPK pathway: a sensor and effector of ribosome homeostasis impairment</td><td>49</td></tr><tr><td>3.1.1.</td><td>The ribotoxic stress response (RSR)</td><td>49</td></tr><tr><td>3.1.2.</td><td>JNK and AMFs: partners in stress response management?</td><td>49</td></tr><tr><td>3.1.3.</td><td>RSR: from cell type specificities to disease</td><td>50</td></tr><tr><td>3.2.</td><td>AMPK-mediated repression of ribosome production</td><td>50</td></tr><tr><td>3.2.1.</td><td>AMPK pathway activation</td><td>50</td></tr><tr><td>3.2.2.</td><td>AMPK-mediated repression of ribosome synthesis</td><td>51</td></tr><tr><td>3.3.</td><td>Ribosome biogenesis surveillance by the p53 signaling pathway</td><td>51</td></tr><tr><td>3.3.1.</td><td>Activation of p53 signaling in response to defects in ribosome production</td><td>51</td></tr><tr><td>3.3.2.</td><td>A negative feedback loop of p53 on ribosome biogenesis</td><td>52</td></tr><tr><td>4.</td><td>Concluding remarks</td><td>52</td></tr><tr><td></td><td>CRediT authorship contribution statement</td><td>53</td></tr><tr><td></td><td>Funding</td><td>53</td></tr><tr><td></td><td>Declaration of competing interest</td><td>53</td></tr><tr><td></td><td>References</td><td>53</td></tr></tbody></table>

# 1. Introduction

Ribosomes are the universal molecular machines ensuring the translation of messenger RNAs into proteins in all living organisms. In eukaryotic cells, they consist of a large (60S) and a small (40S) subunit composed of four ribosomal RNAs (rRNAs) named 5S, 5.8S, 18S and 25S/28S (yeast/human), and about 80 different ribosomal proteins (RPs). Ribosome biogenesis is a massive and complex cellular process initiated in the nucleolus, a membrane-less nuclear domain organized into distinct functional territories, each reflecting the sequential molecular events underlying the early steps of the process. The three transcriptional machineries are mobilized to synthesize the structural components of the ribosomes (4 rRNAs and ~80 RPs), over 200 specialized proteins that facilitate the correct assembly and maturation of ribosomes (the so-called assembly and maturation factors, AMFs), as well as a plethora of small nucleolar RNAs (snoRNAs) involved in rRNA modification and processing. RNA polymerase I (RNA Pol. I) transcribes ribosomal DNA (rDNA) units to synthesize a common precursor to the 18S, 5.8S and 25S/28S rRNAs, while RNA Pol. III generates the precursor to the 5S rRNA. RNA Pol. II synthesizes the mRNAs encoding RPs and AMFs as well as most of the snoRNAs. The process also involves the translation machinery ensuring the synthesis of RPs and AMFs and the nucleo-cytoplasmic transport system for the import and export of ribosome-related materials. During rDNA transcription by RNA Pol. I, the nascent rRNA transcript is packaged with RPs, AMFs and snoRNPs to generate early precursor particles called the pre-ribosomal particles. Conversion of these precursors into the mature, functional ribosomal subunits implicates a complex assembly and maturation process involving the progressive processing of the rRNA precursors into mature rRNAs, the synthesis by snoRNPs of chemical modifications on selected nucleotides, the folding of the rRNAs into a complex 3D structure and the progressive incorporation and stabilization of RPs within this structure. These crucial events are precisely and timely coordinated from the nucleolus to the cytoplasm to ensure the stepwise shaping of the small and large ribosomal subunits into their mature, functional structure before they enter in translation. Ribosome synthesis is among the most energy-consuming cellular processes in eukaryotic cells, and regulatory mechanism have been selected during evolution to precisely adapt this process to the cellular needs depending on extra- and intracellular cues [1–3]. While many reviews in the field focused on the regulation of ribosome synthesis under favorable growth conditions, this review describes specific checkpoints that downregulate ribosome

production and adapt translation to preserve resources and maintain cellular homeostasis under stress. We examine how ribosome stress integrates with major signaling pathways, including the Integrated Stress Response, the Ribotoxic Stress Response, the AMPK pathway, and p53 signaling, which collectively shape cell fate decisions. The nature of these stresses, their key effectors, and their impact on ribosome biogenesis are detailed in each case. For a concise overview, readers may refer to the summary provided in Table 1.

# 2. Impact of cellular stress on ribosome homeostasis

## 2.1. Ribosome biogenesis adaptation in Saccharomyces cerevisiae

### 2.1.1. Transcriptional and post-transcriptional regulations

Specific ribosome synthesis events are subjected to regulation during stress response to ensure an optimal adjustment of the process. In yeast, adaptation to a variety of stresses, including UV exposure, oxidative stress, amino acid starvation and thermal or osmotic shock, converge on a common transcriptional response known as the “Environmental Stress Response” (ESR) (Fig. 1 and Table 1). The activation of ESR is critical for cell viability and is accompanied by a reduced intracellular ribosome content [4]. Key effectors of ESR are the transcription factors Msn2 and Msn4. They activate the transcription of stress-related genes by binding to the Stress Response Element (SRE) of their promoters. This transcriptional reprogramming is coupled with a decreased synthesis of ribosomal rRNAs and mRNAs encoding RPs and AMFs [5–7]. Under stress conditions, coordinated repression of RP and AMF genes requires the recruitment of specific transcription factors to their promoter regions, namely Ifh1, Sfp1, Crf1, Hmo1 and Rap1 [8,9]. This transcriptional repression is accompanied by a reduced stability of mRNAs encoding RPs and AMFs and a rapid degradation of unspliced mRNAs encoding RPs by the Nonsense Mediated Decay (NMD) [5,10]. In the cytoplasm, the Puf family of RNA-binding proteins regulates the stability and translation of mRNAs encoding AMFs under stress conditions. Puf 2/4/5 reduce the stability of AMF mRNAs by binding to a Puf Responsive Element (PRE) located within their 3’UTR, whereas Puf1/3 promote their stability. These findings suggest that expression of different Puf proteins upon stress could contribute to the modulation of AMF expression [11].

Upon proteotoxic stress, such as elevated temperatures, genome-wide studies revealed that Hsf1 activation regulates not only genes containing the heat shock promoter element (HSE) but also genes encoding Rps7/14/21/27 and Rpl26/26L1/35A in yeast.
<caption>**Table 1**</caption>

Summary of the major stress responses in eukaryotes. This table summarizes the major stress responses described in this review, including their triggers, key effectors, and primary targets among ribosome biogenesis factors. When available, relevant details regarding the biological context (e.g., cell lines, experimental conditions) are also provided.

<table><thead><tr><th>Stress response pathway</th><th>Organism</th><th>Cell type</th><th>Trigger(s)</th><th>Effector(s)</th><th>Ribosome biogenesis target(s)</th><th>Reference (s)</th></tr></thead><tbody><tr><td rowspan="10">Environmental stress response (ESR)</td><td rowspan="2">Saccharomyces cerevisiae</td><td>Variety of stress such as starvation, proteotoxic stress, UV exposure</td><td>Unknown</td><td>Repression of genes encoding RPs and AMFs via Ifh1, Sfp1, Crf1, Hmo1 and Rap1</td><td>[5-9]</td></tr><tr><td>Proteotoxic stress</td><td>NMD RP aggregates</td><td>RP mRNA decay Ifh1 and Hsp70 activities</td><td>[5,10] [13]</td></tr><tr><td>Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, Mus musculus, Ratus norvegicus, Homo sapiens</td><td>Proteotoxic stress</td><td>Hsf1/HSF1</td><td>RPS7 (eS7)/14 (uS11)/21 (eS21)/27 (eS27) and Rpl26 (uL24)/26L1 (uL24-like)/35A (eL33) gene transcription</td><td>[12]</td></tr><tr><td>Homo sapiens HeLa, M10, MDA-MB-231, HCT116, Jurkat and HaCaT cell lines</td><td>Proteotoxic stress</td><td>NKRF-XRN2</td><td>Degradation of aberrant pre-rRNA species</td><td>[47]</td></tr><tr><td>Mus musculus and Homo sapiens</td><td>Proteotoxic stress</td><td>Unknown NuRD complex</td><td>Inhibition of TIF-IA phosphorylation (S170/172) Chromatin condensation at the rDNA</td><td>[46]</td></tr><tr><td>HepG2 and MEF cell lines</td><td></td><td>O-GlcNAc cycling enzymes</td><td>O-GlcNAcylation of RPs and ribosome-associated proteins, HSP70 recruitment, proteasome-mediated degradation</td><td>[49]</td></tr><tr><td rowspan="3">Integrated stress response (ISR)</td><td rowspan="2">Saccharomyces cerevisiae</td><td>Variety of stress</td><td>Gcn2</td><td>eIF2α phosphorylation (S51)</td><td>[15-17]</td></tr><tr><td>Oxydative stress</td><td>Aat2</td><td>Interaction with ribosomes to restrict Gcn2 activation</td><td>[19]</td></tr><tr><td>Homo sapiens –</td><td>–</td><td>Snf1</td><td>Hyperactivation triggers nucleolar fragmentation, increases rDNA recombination and the accumulation of rDNA circles</td><td>[99,100]</td></tr><tr><td rowspan="10">Ribotoxic stress response (RSR)</td><td rowspan="2">Saccharomyces cerevisiae</td><td>Variety of stress</td><td>GCN2, PERK, PKR, HRI</td><td>eIF2α phosphorylation (S51)</td><td>[15]</td></tr><tr><td>MCF-7 and MDA-MB-231 cell lines</td><td>AMPK</td><td>Induction of H3K36me2 demethylation by KDM2A leading to chromatin condensation at the rDNA</td><td>[89]</td></tr><tr><td rowspan="2">Mus musculus</td><td>HEK293 cell line</td><td>Glucose deprivation</td><td>TIF-IA phosphorylation (S635)</td><td>[94,95]</td></tr><tr><td>MG63, HeLa and d283 cell lines</td><td>Acute nutrient depletion</td><td>Activation of eEF2K that represses translation elongation</td><td>[98]</td></tr><tr><td rowspan="2">Rattus norvegicus</td><td>In silico screen and in vitro kinase assay</td><td>–</td><td>TCOF1 phosphorylation and DDX56 predicted phosphorylation</td><td>[96]</td></tr><tr><td>NB1RGB, HEK293, HCT116, H1299, A549, U2OS, and HeLa cell lines</td><td>Glucose/nutrient deprivation</td><td>H3 deacetylation and K9 dimethylation at the rDNA reinforce chromatin condensation</td><td>[90,91]</td></tr><tr><td rowspan="2">Mus musculus</td><td>HaCaT, SiHa and CaLo cell lines</td><td>SIRT1</td><td>Acetylation of RNA Pol. I components, AMFs and RPs</td><td>[92]</td></tr><tr><td>NIH3T3 cell line, γ2-AMPK cardiac KO mouse model (in vivo)</td><td>Glucose deprivation</td><td>AMPK</td><td>TIF-IA phosphorylation (S635)</td><td>[94,95]</td></tr><tr><td rowspan="2">Rattus norvegicus</td><td>Xenografts into nude mice (in vivo)</td><td>Acute nutrient depletion</td><td>AMPK</td><td>Activation of eEF2K that represses translation elongation</td><td>[98]</td></tr><tr><td>Primary hepatocytes</td><td>Exercise</td><td>AMPK</td><td>Decrease of 4EBP phosphorylation and repression of 5'TOP mRNA translation</td><td>[97]</td></tr><tr><td rowspan="2">Saccharomyces cerevisiae</td><td>Amino acid starvation, alkylative stress and genotoxic stress</td><td>Mbf1</td><td>Association with ribosomes for robust activation of the ISR response</td><td>[74]</td></tr><tr><td>Homo sapiens HEK293T and HEK293E cell lines</td><td>PMA and UV exposure</td><td>JNK</td><td>eEF1A2 phosphorylation (S205/358) and degradation of newly synthesized polypeptides</td><td>[70]</td></tr><tr><td rowspan="2">Mus musculus and Homo sapiens</td><td>HEK293 and HT-1080 cell lines</td><td>Actinomycin D, UV exposure and Anisomycin</td><td>c-Jun</td><td>DDX21 nucleoplasmic re-localization</td><td>[76]</td></tr><tr><td>MEF and HEK293T cell lines</td><td>Anisomycin and H2O2</td><td>JNK</td><td>Interaction with DDX21 for transcriptional reprogramming</td><td>[76]</td></tr><tr><td rowspan="5">Nucleolar stress response</td><td>Mus musculus</td><td>MEF, mouse fibroblast and NIH3T3 cell lines</td><td>UV exposure</td><td>c-Jun</td><td>TIF-IA phosphorylation (T200)</td><td>[75]</td></tr><tr><td>Homo sapiens</td><td>HeLa and H1299 cell lines</td><td>–</td><td>p53</td><td>Interaction with B23/NPM</td><td>[79]</td></tr><tr><td rowspan="2">Mus musculus</td><td>HeLa and H1299 cell lines</td><td>Methane methylsulfonate</td><td>p53</td><td>Interaction with TBP and TAF110 to inhibit RNA Pol. I initiation of transcription</td><td>[116]</td></tr><tr><td>Various cancer cell types</td><td>–</td><td>p53</td><td>RNA Pol. III transcription inhibition</td><td>[118-120]</td></tr><tr><td rowspan="2">Mus musculus</td><td>HCT116, HT-29, MRC-5, H1299, MCF7, WI38, SVV138 and CaSki cell lines</td><td>Actinomycin D, Doxorubicin</td><td>p53</td><td>rDNA integrity</td><td>[121]</td></tr><tr><td>MCO1/cG9-6 cell lines</td><td>–</td><td>p53</td><td>Inhibition of Importin 7 and CRM1 gene transcription</td><td>[122,123]</td></tr><tr><td rowspan="2">Mus musculus</td><td>WT and p53 KO immortalized 3T3 fibroblast and MEF cell lines</td><td>–</td><td>p53</td><td>RNA Pol. I transcription inhibition</td><td>[117]</td></tr><tr><td></td><td></td><td>p53</td><td>RNA Pol. III transcription inhibition</td><td>[119,120]</td></tr></tbody></table>

(continued on next page)
<table><caption>**Table 1** (continued)</caption><thead><tr><th>Stress response pathway</th><th>Organism</th><th>Cell type</th><th>Trigger(s)</th><th>Effector(s)</th><th>Ribosome biogenesis target(s)</th><th>Reference (s)</th></tr></thead><tbody><tr><td rowspan="2">mPOS</td><td rowspan="2">Saccharomyces cerevisiae</td><td>WT and p53 KO MEF cell lines –</td><td rowspan="2">Mitochondrial damages</td><td rowspan="2">Unknown</td><td><strong>Inhibition of Importin 7 and CRM1 gene transcription</strong></td><td>[122]</td></tr><tr><td></td><td><strong>Nog2 and Gis2: negative feedback loop to promote survival</strong></td><td>[30]</td></tr></tbody></table>

<figure><img src="image_2.png" /><figcaption>**Fig. 1.** Cellular stress responses activated under stress conditions</figcaption></figure>

Three main pathways are activated upon stress. The Environmental Stress Response (ESR) involves transcription factors Msn2 and Msn4 that activate the expression of stress-related genes containing Stress Response Element (SRE) in their promoter region. ESR is yeast-specific, but mammals harbor functionally equivalent transcriptional responses to stress. In mammals, the Integrated Stress Response (ISR) triggers a translational reprogramming initiated by the phosphorylation of the translation initiation factor eIF2α at serine 51 (S51). A functionally analogous pathway operates in S. cerevisiae, via the Gcn2 kinase, which phosphorylates eIF2α (Sui2). In mammals, the Ribotoxic Stress Response (RSR), triggered by ribosome stalling or collisions, leads to the activation of the Stress-Activated Protein Kinase (SAPK) and to GCN2-mediated phosphorylation of eIF2α to initiate the ISR. SAPK activation dampens mTOR activity and promotes AMPK activation through downstream JNK signaling. No canonical RSR is found in yeast, but analogous responses exist via Hog1 (a p38-like MAPK). See the main text for more details.

Interestingly, these RP genes are also HSF1 targets in human cells (Fig. 2), suggesting an evolutionarily conserved regulatory mechanism. Although no additional information is available yet, it is tempting to speculate that the transcriptional regulation of specific RPs contributes to proteostasis recovery [12]. Ribosome biogenesis status is also tightly linked to Hsf1 activation. Upon stress, defects in ribosome biogenesis lead to the accumulation of nucleolar proteins, forming aggregates that are recognized by the chaperone Hsp70. As a consequence, Hsp70 dissociates from Hsf1, which allows the recruitment of Hsf1 to its target genes to initiate transcriptional reprogramming [13]. In parallel, the sequestration of TorC1 complex into stress granules prevents the premature resumption of ribosome biogenesis, ensuring a coordinated cellular response to stress [14].

### 2.1.2. Translational reprogramming

#### 2.1.2.1. Activation of the integrated stress response (ISR).
In both yeast and mammals, a rapid adaptive response upon stress sensing is the activation of the integrated stress response (ISR) to restore homeostasis (Fig. 1 and Table 1). ISR acts at the translation level and is initiated by phosphorylation of the translation initiation factor eIF2α at serine 51 (S51) by Gcn2 in yeast. In mammals, this phosphorylation event is orchestrated by four different kinases according to stress stimuli [15]. Phosphorylated eIF2α inhibits eIF2B activity leading to a global impairment of translation initiation, along with the translation activation of a specific subset of

mRNAs [16]. In particular, Gcn2-mediated eIF2α phosphorylation induces the translation of the mRNA encoding Gcn4. In turn, Gcn4 stimulates the transcription of genes responsible for stress recovery [17].

Maintaining the proper balance of eIF4F complex components, particularly eIF4A and eIF4E, is important for the regulation of ISR and especially the proper repression of the mRNA encoding Gcn4 in normal condition. The aberrant expression of Gcn4 when this balance is disrupted occurs via an uncharacterized mechanism, independent of eIF2α phosphorylation [18]. In yeast, upon oxidative stress, Aat2, an aspartate aminotransferase, restricts Gcn2 activation and the ISR by directly interacting with ribosomes. This regulation influences yeast sensitivity to oxidative damage, and is independent of Aat2 enzymatic activity [19].

#### 2.1.2.2. Hibernating and specialized ribosomes.
In S. pombe, prolonged glucose deprivation leads to a shutdown of translation, resulting in the accumulation of inactive 80S ribosomes that are not associated with mRNAs and tRNAs. It has been proposed that a 60° rotation of the rRNA helix 69 (H69) in domain IV of the large ribosomal subunit self-inhibits de novo tRNA loading and translational activity. These locked 80S ribosomes, also referred to as hibernating ribosomes, are tethered to the outer membrane of fragmented mitochondria thanks to the AMF/translational factor RACK1 in distinct oligomeric ribosome forms [20]. This hibernation mechanism is reminiscent of RNA Pol. I hibernation state
<figure><img src="image_3.png" /><figcaption>**Fig. 2.** Regulation of ribosome biogenesis upon heat shock
Pathways occurring upon heat shock in mammals. Black bubbles schematize the different ribosome biogenesis steps. Heat shock activates HSF1, which promotes the transcription by RNA Pol. II of genes containing the Heat Shock Promoter element (HSE) and a subset of genes encoding RPs. Heat shock prevents phosphorylation of TIF-IA and reduces RNA Pol. I recruitment at the rDNA loci. This allows RNA Pol. II to transcribe PAPAS lncRNAs that recruit the NuRD complex and trigger nucleosome repositioning to strengthen the inhibition of RNA Pol. I transcription initiation. HSF1 also induces the expression of NKRF that interacts with the exoribonuclease XRN2 to prevent the accumulation of toxic aberrant pre-rRNA species. See the main text for more details.</figcaption></figure>

observed under nutrient deprivation stress, where the dimerization of the enzyme prevents its activation until favorable growth conditions return [21]. Although the mechanisms at the origin of hibernating ribosome reactivation remain uncharacterized so far, it may involve post-translational modifications, as for RNA Pol. I [21]. The hibernation mode of these two machineries has probably evolved to enable a rapid resumption of RNA Pol. I transcription and translation after overcoming cellular stress. This underlines the crucial involvement of these two activities in the early stages of stress recovery.

Increasing evidence reveals that an heterogeneity of ribosome composition is crucial to modulate the translation toward specific mRNA subsets [22,23]. One of the best-characterized examples of such specialized ribosomes are mature ribosomes devoid of the small subunit ribosomal protein (Rps) 26, which play a key role in stress-associated translation reprogramming. Rps26-deficient ribosomes exhibit reduced affinity for mRNAs containing the canonical Kozak sequence, important for translation initiation. Instead, they preferentially translate low-abundance mRNAs with longer 5'UTRs and ORFs, including those encoding components of the Hog-MAPK pathway (critical for hyperosmotic stress response), the Rim101 pathway (partially contributing to pH adaptation) and factors involved in cell wall integrity [24]. Accordingly, production of Rps26-deficient ribosomes was proposed to play an important role in the resistance to high salt and high pH stress [24,25]. Upon stress, Rps26 is removed from the mature small ribosomal subunits by the chaperone Tsr2. Free Rps26 can then be either stabilized by Tsr2 to prevent proteolysis, or targeted for degradation via the Pro/N-degron pathway to prevent its reincorporation into 40S particles [25–27]. Recognition of the Kozak sequence by the small ribosomal subunit plays a key role in stress-induced translation regulation. Introduction of point mutations within the Kozak sequence of an mRNA is sufficient to promote its translation by Rps26-deficient ribosomes. The emergence of point mutations within the 5'UTR of key mRNAs may thus represent a mechanism acquired during evolution to optimize stress response management [28].

RPs are particularly sensitive to H₂O₂-mediated oxidative stress, with Rps26 and the large subunit ribosomal protein (Rpl) 10 being the most affected ones. Upon H₂O₂ exposure, these proteins

exhibit increased cysteinyl oxidation. In the case of Rps26, this oxidation leads to the release of its Zn²⁺ ion from the Zinc-finger motif, likely impairing its function. Oxidized Rps26 and Rpl10 are recognized by the chaperone proteins Tsr2 and Sqt1, respectively, which facilitate their removal from 80S ribosomes. Over time, newly synthesized, non-oxidized RPs are reincorporated into mature ribosomes through an as-yet unknown mechanism, while oxidized forms are degraded [29]. It is tempting to speculate that the transient removal of these RPs from the ribosomes allows for the formation of ribosomes specialized in the oxidative stress response. A complementary study indicates that, following oxidative stress, Rpl8, Rps2 and Rps10 are less represented within actively translating ribosomes (polysomes) while Rpl7 and Rpl38 appear more enriched [19]. As for Rps26-deficient ribosomes, further characterization of these composition changes might reveal new critical roles for these RPs during translation. Importantly, these recent findings place Rps26 as a central cellular stress sensor and integrator, given its higher sensitivity to oxidative stress and its pivotal role in stress-associated translational reprogramming.

2.1.2.3. Additional regulatory mechanisms under oxidative stress.
Mitochondrial dysfunction activates the mitochondrial Precursor Over-accumulation Stress (mPOS) pathway, which arises from cytoplasmic accumulation and misfolding of mitochondrial precursor proteins, ultimately triggering mitochondria-mediated cell death. Once mPOS is activated, two ribosome-related factors orchestrate a negative feedback loop to attenuate mPOS-mediated cell death: the pre-60S particle AMF Nog2 and the activator of IRES-mediated translation Gis2 [30] (Table 1). The AMF/translation factor Rli1 (the orthologue of human ABCE1) also contributes to oxidative stress resistance [31]. Although Gis2 and Rli1 are thought to promote survival via a modulation of translation, the mechanism by which Nog2 confers its protective effect remains unclear.

Upon oxidative stress, the accumulation of reactive oxygen species (ROS) affects ribosome integrity by altering rRNA structure. One driver of oxidative stress is the disruption of iron homeostasis. Under this condition, increased level of Fe²⁺ promotes the conversion of H₂O₂ into hydroxyl radical (·OH). Ribosomal RNA interacts with Mg²⁺ and it has been proposed that accessible Mg²⁺
ions exposed to the solvent-facing side of the ribosome are pref-
erentially replaced by Fe²⁺, leading to site-specific chemical
cleavage of the rRNAs upon ROS accumulation. A prominent
cleavage site is located in the expansion segment ES7 of the 25S
rRNA, exposed on the surface of the 60S subunit. The integrity of
the 18S, 5S and 5.8S rRNAs appears less affected by ROS accumu-
lation, although these findings require further investigations [32].

## 2.2. Stress-induced shut down of ribosome production in mammalian cells

2.2.1. Nucleolar oxidation

In humans, a variety of stresses, such as exposure to H₂O₂, low oxygen (hypoxia), UVs, drugs such as actinomycin D or heat shock, directly affects nucleolar activities and leads to an increase in ROS species in the nuclear body, causing a nucleolar oxidation [33,34]. This oxidation induces the S-glutathionylation of the nucleolar AMF NPM1/B23 at cysteine 275. This post-translational modification induces NPM1/B23 nucleoplasmic re-localization, where it contributes to the activation of p53 signaling [33]. In parallel, a nucleolar stress is reflected by a lower ratio of nucleolar nucleolin to nucleolar UBF compared to normal conditions [34].

2.2.2. rDNA transcription and rRNA processing

Depending on the origin of the cellular stress, different sensing
mechanisms have evolved in mammalian cells to ensure a rapid
shut down of rDNA transcription and ribosome activity.

Oxidative stress and UVs increase the cleavage of the trans-
membrane (cytoplasmic membrane) β-dystroglycan (β-DG) pro-
teins. The intracellular domain of β-DG proteins is then released
into the cytosol and addressed to the nucleolus, where it binds to
rDNA regions and helps inhibiting pre-rRNA synthesis. This inhi-
bition is in part attributed to a reduced expression and mis-
localization of the transcription factor UBF [35]. UV irradiation also
induces nucleolar segregation, causing RNA Pol. I and fibrillarin to
relocate into compact regions at the nucleolar periphery, forming
nucleolar caps. This process is accompanied by the release of the
proliferation marker Ki-67 from the nucleolus [36].

Hypoxia downregulates RNA Pol. I transcription via the car-
bonic anhydrase IX (CA IX) metalloenzyme. While CA IX binds to
nucleolar rDNA loci when oxygen levels are normal, this associa-
tion is prevented by CRM1 interaction with CA IX in the nucleolus
and at the nuclear membrane under hypoxia [37,38]. This regula-
tion could affect ribosome production by simultaneously reducing
RNA Pol. I activity and impairing CRM1-mediated export of pre-
ribosomal particles. Hypoxia also leads to the inhibition of RNA
Pol. III transcription. Low oxygen levels impair the interaction of
transcription factor III B (TFIIIB) with c-Myc and ERK, leading to its
sequestration by Rb [39].

Upon replicative stress, SLFN11, a t-RNA endoribonuclease with
a putative DNA/RNA helicase activity, downregulates both RNA Pol.
I transcription and mRNA translation. The molecular mechanisms
underlying rRNA synthesis repression require further in-
vestigations. Three structural domains of SLFN11 are critical for its
inhibitory function: its Walker B motif (E669), its RNase catalytic
domains (E209/E214) and its single stranded DNA (ssDNA)-bind-
ing site (K652). It also requires the dephosphorylation of SLFN11 at
S753, a site known to regulate its binding to ssDNA (S753). In
parallel, SLFN11 promotes JNK signaling and reduces the cyto-
plasmic accumulation of the anti-apoptotic protein MCL1, which
leads to apoptosis [40]. Upon genotoxic stress, the expression of

RPS3 is also deleterious for cells. This toxic effect of RPS3 certainly
results from its accumulation as free protein (i.e. less associated
with ribosomal particles) that fulfils extra-ribosomal functions. In
particular, RPS3 displays a high affinity for the 8-oxoG DNA dam-
age mark, one of the most prevalent modifications induced by ROS.
RPS3 is thought to be detrimental for genotoxic stress manage-
ment in part by interacting with these DNA damage marks and
impairing their repair [41-45].

Heat shock sensing elicits a specific cascade of events to halt rRNA synthesis and restore protein homeostasis (Fig. 2). The repression of rRNA synthesis is ensured by the inhibition of RNA Pol. I pre-initiation complex (PIC) formation along with a local epigenetic remodeling of the rDNA loci. Heat shock prevents phosphorylation of the transcription factor TIF-IA at S170/172 by casein kinase 2. This impairs RNA Pol. I interaction with TIF-IA and reduces its recruitment at the rDNA loci. Reduction of RNA Pol. I occupancy on the rDNA allows RNA Pol. II recruitment and the transcription of the promoter and pre-rRNA antisense (PAPAS) lncRNA. In turn, PAPAS lncRNA recruits the Nucleosome Remod-eling and Deacetylation (NuRD) complex. NuRD triggers nucleo-some repositioning that fully represses the initiation of transcription [46]. At the post-transcriptional level, elevated temperature induces HSF1-mediated expression of NF-κB Repressing Factor (NKRF). NKRF plays a key role in the mainte-nance of nucleolar homeostasis through its interaction with the 5'-to-3' exoribonuclease XRN2. XRN2 is involved in the normal pro-cessing and degradation of rRNA precursors. The NKRF-XRN2 complex handles the degradation of aberrant pre-rRNA species, whose accumulation becomes toxic upon heat shock. NKRF would directly regulate XRN2 trafficking between the nucleolus and nucleoplasm [47]. The kinetics of pre-rRNA processing appear to be particularly sensitive to temperature change. Mild hypothermia (32 °C) also alters pre-rRNA processing, causing an accumulation of several pre-rRNAs species. These defects are in part due to cold-induced sumoylation of the 3'-to-5' exoribonuclease EXOSC10, the orthologue of yeast Rrp6, which reduces its expression level [48]. In parallel, proteotoxic stress promotes the O-linked N-acetylglu-cosamine (O-GlcNAc) glycosylation of ribosome-associated pro-teins. This post-translational modification is especially important for the optimal recruitment of the chaperone Hsp70 to ribosomes, and the proper ubiquitination and proteasome-mediated degra-dation of ribosome-associated components [49].

2.2.3. RP gene expression

Transcriptomic analysis across different murine brain regions
revealed that RP gene expression varies depending on stress type,
with fluctuations more pronounced under chronic stress condi-
tions than acute ones [50]. This transcriptional regulation is most
likely connected to the presence of RP pseudogenes, because RP
gene downregulation correlates with their upregulation [51]. Un-
der stress conditions, RP expression is mainly regulated at the
translational level [52]. mRNAs encoding RPs belongs to the 5'
terminal oligopyrimidine (5'TOP) mRNAs subclass, whose trans-
lation inhibition is more pronounced than other mRNAs upon
stress [53-56]. The presence of this oligo tract allows the recruit-
ment of specific *trans*-acting factors such as LARP1, TIA-1 and TIAR,
which stabilize 5'TOP mRNAs, repress their translation and direct
their relocation to stress granules or P-bodies [57-61]. In the stress
granules, ribosomes can pursue 5'TOP mRNA translation [62], most
likely to optimize RP supply upon recovery or upregulate the level
of specific RPs.
# 3. Signaling pathways regulating ribosome biogenesis under stress conditions

## 3.1. SAPK pathway: a sensor and effector of ribosome homeostasis impairment

### 3.1.1. The ribotoxic stress response (RSR)

The Stress-Activated Protein Kinase (SAPK) signaling pathway comprises JNK and p38 MAPK (Hog1 in yeast) signaling. SAPK activation is initiated by an impairment of ribosome homeostasis and starts with the activation of a MAPKKK, such as ZAKα, which phosphorylates and activates the MAPKK MKK, ultimately leading to the activation of the JNK and p38 MAPK signaling cascades (Fig. 3). While similar stressors can activate both JNK and p38, they often exhibit distinct temporal activation patterns and can lead to different cellular outcomes upon cellular stress. JNK primarily phosphorylates c-Jun and activates AP-1 transcription factors, while p38 targets multiple substrates including MAPKAPK2 and

various transcription factors. These pathways play a dual role in cell fate, promoting either apoptosis or cell survival and proliferation, depending on intra cellular events [63,64].

Ribotoxic stressors, such as UVs, amino acid deprivation, ricin, anisomycin and nitric oxide (NO) induce the activation of JNK and p38 signaling pathways via the ribotoxic stress response (RSR) (Figs. 1 and 3, and Table 1). Ribosomes stalled in translation or in collision with other elongating ribosomes lead to the activation of the ribosome-associated MAPKKK ZAKα through autophosphorylation. ZAKα docks onto ribosomes via its C-terminal domain (CTD) that directly interacts with helix H14 of the 18S rRNA. The kinase senses ribotoxic stress via another ribosome-interacting region termed "sensing domain", also present in the C-terminal part of the protein. Phosphorylated ZAKα then activates downstream MAPKK, leading to the activation of the effector kinases JNK and p38 MAPK, which coordinate the stress response [65–69]. Both JNK and p38 are associated with ribosomes, either for their activation or function, suggesting that ribosomes play a role at several stages of SAPK signaling [70,71]. Notably, JNK activation relies on its interaction with the AMF/translation factor RACK1, which recruits the kinase to ribosomes. Once there, JNK phosphorylates eEF1A2 to adjust translational activity and promote the degradation of newly synthesized polypeptides (NSPs) [70,72]. Upon UV irradiation, RPS3 interacts with the apoptosis activator TRADD, further contributing to JNK activation [73]. In parallel to SAPK activation, ribosome collisions trigger GCN2-mediated phosphorylation of eIF2α to initiate the ISR [66,67]. In yeast, optimal ISR activation upon ribosome collision requires the recruitment of Mbf1, which binds stalled ribosomes via its N-terminal domain [74].

SAPK signalling is finely tuned by two negative feedback loops that restrain ZAKα activation. First, GCN2-driven translation adaptation/shutdown reduces colliding ribosomes, thereby decreasing ZAKα recruitment and activation. Second, ZAKα phosphorylation directly impacts its association with the small ribosomal subunit and its stability. Phosphorylation occurs within a cluster of serine residues adjacent to its ribosome binding region (RBR), inducing its dissociation from the ribosome. Within this cluster, the phosphorylation of two specific serine residues (⁶⁵⁶DSGFSS⁶⁶¹) acts as a phosphodegron directing ZAKα interaction with ubiquitin ligase and subsequent degradation [68].

### 3.1.2. JNK and AMFs: partners in stress response management?

Once activated, JNK represses RNA Pol. I transcription by inactivating TIF-IA through its phosphorylation at threonine 200 (T200) [75] (Fig. 3). In parallel, JNK promotes the re-localization of AMF DDX21 from the nucleolus to the nucleoplasm. In the nucleoplasm, DDX21 interacts with JNK downstream effector c-Jun, a key transcription factor and major component of the AP-1 complex that regulates genes involved in cell proliferation, differentiation, and apoptosis in response to cellular stress. The interaction between DDX21 and c-Jun is important for c-Jun-driven transcriptional activity [76]. Surprisingly, upon favorable growth conditions, the inhibition of the JNK pathway also induces DDX21 re-localization to the nucleoplasm. This is accompanied by a reduced association of DDX21 with pre-60S particles and a decrease in the steady state levels of mature 28S and 18S rRNAs. These defects are largely attributed to a diminished basal interaction between DDX21 and c-Jun [77,78]. These findings suggest that the JNK pathway plays a dual role in the regulation of ribosome synthesis, depending on its level of activation: low signaling supports the proper maturation of pre-ribosomal particles, while acute activation during stress inhibits this process. In addition to DDX21, c-Jun has also been reported to interact with another AMF, B23/NPM, which translocates from the nucleolus to the

<figure><img src="image_4.png" /></figure>

**Fig. 3.** Connections between SAPK signaling and ribosome-associated processes Scheme depicting the activation of SAPK signaling upon ribotoxic stress and the downstream impact on ribosome biogenesis in mammals. Black bubbles schematize the different ribosome biogenesis steps. Ribosome stalling or colliding activate ZAKα (MAPKKK), which phosphorylates MKK (MAPKK), leading to the activation of the JNK and p38 MAPK effector kinases. Ribosome collisions also trigger GCN2-mediated phosphorylation of eIF2α to initiate the ISR and decrease global translation. Once activated, JNK represses RNA Pol. I transcription by inactivating TIF-IA through phosphorylation. JNK also phosphorylates c-Jun, a key transcription factor of the AP-1 complex, which regulates RNA Pol. II transcription. c-Jun functions in association with the nucleolar AMF DDX21 that relocalizes to the nucleoplasm under stress conditions. This is accompanied by a reduced association of DDX21 with pre-60S particles and a decrease in the steady state levels of mature 28S and 18S rRNAs. c-Jun also interacts with AMF B23/NPM but the functional significance of this association remains unclear. See the main text for more details.
nucleoplasm upon JNK signaling activation [79]. However, the
contribution of B23-c-Jun interaction to c-Jun activity remains to
be explored. Under stress conditions, nucleolar disorganization
triggers the nucleoplasmic re-localization of several other AMFs. It
will be exciting to evaluate whether additional factors contribute
to the transmission of the stress response.

Ribosomes frequently experience transient collisions when present on the same mRNA [80]. While it remains unclear whether these collisions are sufficient to activate ZAKα, they may contribute to the basal activation of SAPK signaling, a mechanism proposed to enhance stress-response efficiency in yeast and which appears to ensure proper ribosomal particle maturation in human cells [77,78,81].

3.1.3. RSR: from cell type specificities to disease

The RSR cascade constitutes a key cellular sensor driving
cellular identity and cell survival. In mammals, the integration of
amino acid deprivation via ZAKα signaling leads to the generation
of fetal-like Lgr5-negative intestinal stem cells. These stem cells
display a metabolic switch that is proposed to allow proper in-
testine adaptation to diet restriction [82]. In parallel, ZAKα acti-
vation modulates metabolic pathways by dampening mTOR
activity and promoting AMPK activation through JNK signaling.
The presence of ZAKα is especially required for proper white adi-
pose tissue maintenance, a central metabolic organ [69]. These
insights underscore the role of translational disturbances—not
merely as markers of impaired protein synthesis—but as key
sensors that integrate cellular nutrient status with metabolic
homeostasis.

Ribosome-targeted cancer treatments are in rapid develop-
ment [83]. For some of them generating ribotoxic stress, like
homoharringtonine (HHT), cancer cells from solid tumors exploit
the RSR to survive. RSR leads to the formation of Snail1-USP36
complex, which relocalizes in the nucleolus to promote rRNA
synthesis and tumor growth. The absence of the Snail1-USP36 axis
in leukemic cells, due to a low expression of USP36, renders them
sensitive to HHT and provides an insight into why HHT is only
promising in liquid tumors [84].

These exciting new findings on the RSR cascade suggest that an impairment of ribosome homeostasis not only acts as a general stress response but also elicits cell-type specific cellular cascades controlling cell fate. This raises important questions regarding the connections between RSR activity and the pathophysiology of ribosomopathies, a rare disorder characterised by a chronic impairment of ribosome homeostasis [85]. In particular, it remains unknown what is the state of the RSR response in ribosomopathy patients and to what extent a chronic imbalance in ribosome homeostasis influences stress management at the cellular and organismal level.

3.2. AMPK-mediated repression of ribosome production

3.2.1. AMPK pathway activation

AMP-activated Kinase (AMPK), also called Sucrose Non-
Fermenting 1 (Snf1) in yeast and SNF1 Related Kinase 1 (SnRK1)
in plants, is an evolutionarily conserved kinase that orchestrates
cellular energy homeostasis. Usually, AMPK functions as a hetero-
trimer, which is composed of a catalytic subunit α in association
with two regulatory subunits, β and γ. In human cells, different
genes encode different isoforms for each subunit, α1/2, β1/2, γ1/2/
3, thereby leading to at least 12 different combinations of AMPK
complexes [86]. In mammals, AMPK is activated by an increase in
the AMP/ATP ratio, which may result from glucose deprivation,
hypoxia or oxidative stress (Fig. 4). Activation of AMPK is induced
by its phosphorylation by both LKB1 and CaMKKβ. In parallel,

<figure><img src="image_5.png" /><figcaption>Fig. 4. AMPK and inhibition of ribosome biogenesis</figcaption></figure>

Scheme of the events repressing ribosome biogenesis upon AMPK activation in mammals. Black bubbles schematize the different ribosome biogenesis steps. AMPK is activated by an increase of the cellular AMP/ATP ratio, which may result from glucose deprivation, hypoxia or oxidative stress. Its activation is induced by both LKB1- and CaMKKβ-dependent phosphorylation and allosteric activation of the kinase by AMP binding. Activated AMPK directly phosphorylates SIRT1, which initiates a positive feedback loop by deacetylating the AMPK-activating kinase LKB1, which leads to increased activities of both LKB1 and AMPK. Upon activation, SIRT1 and AMPK cooperate to repress rDNA transcription. SIRT1 belongs to the eNoSC silencing complex in association with the pre-60S AMF Nucleomethylin (NML) and the histone-lysine methyltransferase SUV39H1, which is targeted to the rDNA loci to reinforce rDNA chromatin condensation. AMPK phosphorylates TIF-IA, which impairs its interaction with SL1 and the initiation of RNA Pol. I transcription. AMPK may also directly regulate the post-transcriptional steps of ribosome synthesis by phosphorylating DDX56 and TCOF1 (dotted arrow). In the rat liver, activation of AMPK represses the translation of 5'TOP-containing mRNAs encoding proteins related to translation, by lifting the inhibition of 4EBP, a negative regulator of the cap-dependent translation. Under acute nutrient depletion, AMPK activates eEF2 Kinase (eEF2K) that inhibits translation elongation by targeting eEF2. See the main text for more details.

binding of AMP to AMPK γ subunit induces an allosteric activation
of the kinase. Upon activation, AMPK limits anabolic energy-
consuming processes to save energy and stimulates catabolic
processes like autophagy, glycolysis and fatty acid oxidation. This
kinase orchestrates systemic metabolism homeostasis. In the hy-
pothalamus, it integrates both hormonal and nutritional signals to
adjust food intake and body weight. When blood glucose level is
low, AMPK is also responsible for inhibition of insulin secretion by
the pancreatic β cells [86]. AMPK is a well-known inhibitor of the
mTORC1 pathway, which is directly correlated with the energy
status of cells. Activated AMPK prevents mTOR activation by
enhancing TSC2 activity, a negative regulator of mTOR [87]. AMPK
also influences the epigenetic landmarks. It directly phosphory-
lates histones and targets histone-modifiers, such as histone ace-
tyltransferases (HATs) and histone deacetylases (HDACs), to
facilitate the transcription of stress response genes. For example,
AMPK increases intracellular NAD+ levels, thereby activating
NAD+-dependent protein deacetylases SIRTUINS (SIRT1-7). In
parallel, SIRT1 is directly phosphorylated by AMPK, which releases
SIRT1 from its inhibitor DBC1. Once activated, SIRT1 initiates a
positive feedback loop by deacetylating the AMPK-activating ki-
nase LKB1, which leads to increased activities of both LKB1 and
AMPK. SIRT1 establishes repressive histone marks, both directly by
deacetylating histones (e.g. H4K16) or indirectly by modulating
the activity of other histone-modifying enzymes like the histone-
lysine methyltransferase SUV39H1 [88].

3.2.2. AMPK-mediated repression of ribosome synthesis

Upon AMPK activation, both AMPK and SIRT1 activities coop-
erate to repress rDNA transcription (Fig. 4 and Table 1). In mild
glucose starvation conditions, activation of AMPK induces the
demethylation of H3K36me2 by KDM2A at the rDNA loci, which
results in chromatin condensation [89]. During glucose depriva-
tion, SIRT1 protects cells from apoptosis by reinforcing rDNA
repression. SIRT1 belongs to the energy-dependent Nucleolar
Silencing Complex (eNoSC), in association with Nucleomethylin
(NML) and SUV39H1. In normal conditions, NML is present in pre-
60S particles, where its interaction with pre-rRNA prevents its
association with SIRT1. During glucose deprivation, reduction of
pre-rRNA synthesis reduces the proportion of NML bound to pre-
ribosomes. Free NML then interacts with SIRT1, which addresses
the eNoSC complex to the rDNA loci. There, SIRT1 and SUV39H1
reinforce rDNA chromatin condensation through H3 deacetylation
and dimethylation of its lysine K9, respectively [90,91]. In addition,
SIRT1 inhibition increases the level of lysine acetylation in proteins
involved in ribosome biogenesis (RNA Pol. I components, AMFs
and RPs), suggesting that SIRT1 deacetylase activity may also
directly target key players of ribosome synthesis and translation to
down-regulate the whole process [92]. In particular, such post-
translational modifications could contribute to the compaction
of the nucleolus and RNA Pol. I nucleolar sequestration that is
driven by lysine-rich nucleolar proteins [93].

Under glucose deprivation conditions, AMPK not only induces rDNA chromatin changes, but also phosphorylates TIF-IA at S635, which impairs its interaction with SL1 and the initiation of RNA Pol. I transcription [94]. In heart cells, this inhibitory phosphorylation of TIF-IA is mediated by AMPK complexes containing isoform 2 of the γ subunit and is important to reduce ER stress and cell death. This observation supports the importance of shutting down ribosome production upon unfavorable conditions [95]. A combination of *in silico* screens and *in vitro* kinase assays identified AMFs DDX56 and TCOF1 as AMPK substrates [96]. This suggests that AMPK can also directly regulate ribosome synthesis at the post-transcriptional level.

AMPK activation also impairs RP expression by modulating
translation initiation and elongation. In the rat liver, following
exercise-mediated reduction of cellular resources, the activation of
AMPK represses the translation of 5'TOP mRNAs. Interestingly,
among the 5'TOP mRNAs, only those encoding proteins related to
translation (eIF1A, RPS6/8) seem to be affected, without changes in
the efficiency of translation of other mRNAs encoding, for example,
β-actin and GAPDH. This repression is linked to a decrease of 4EBP
phosphorylation that impairs the interaction between two factors
involved in cap-dependent translation initiation, eIF4E and eIF4G
[97]. Under acute nutrient depletion, AMPK activates eEF2 Kinase
(eEF2K) that inhibits translation elongation by targeting the
translation elongation factor eEF2. This AMPK-eEF2K axis appears
particularly exploited by cancer cells, for long-term survival upon
metabolic stress [98].

Interestingly, in yeast, the absence of Sip2, the orthologue of
mammalian AMPK β subunit, accelerates appearance of aging
markers and decreases lifespan. Accelerated aging results from a
hyper-activation of Snf1 kinase, the yeast orthologue of AMPK α
subunit. This phenotype is characterized by a nucleolar fragmen-
tation and a high level of rDNA recombination that induces accu-
mulation of extra-chromosomal rDNA circles (ERCs). The absence
of Sip2 can be rescued by deleting the activator subunit Snf4 (yeast

orthologue of AMPKγ). Further analyses indicate that in young
cells, Sip2 prevents aging by anchoring Snf4 to the plasma mem-
brane, thereby sequestering the protein in the cytoplasm. Snf4
sequestration limits rDNA recombination levels responsible for
premature aging upon Snf1 hyper activation [99,100]. These
studies indicate that appropriate regulation of AMPK activity is
necessary for rDNA integrity and suggests that rDNA integrity by
itself is a new driving factor for aging. In agreement with this,
nucleolar expansion correlates with accelerated aging in yeast, C.
elegans and humans [101–103].

3.3. Ribosome biogenesis surveillance by the p53 signaling pathway

Several stress responses converge on p53 to drive cell cycle
arrest and determine cell fate. Under normal conditions, p53 levels
remain low due to MDM2-mediated ubiquitination and protea-
somal degradation. Stress, such as DNA damage, expression of
oncogenes, ribosome synthesis defects or hypoxia, stabilize p53,
preventing its degradation either via direct post-translational
modifications or MDM2 inhibition [104]. Accumulated p53
blocks the cell-cycle by inducing the expression of key effectors,
such as the cyclin-dependent kinase inhibitor p21 and 14-3-3σ.
Stress duration influences the cellular outcomes (recovery,
senescence or apoptosis) mediated by several p53 targets and
feedback loops fine-tune the p53 response [104,105].

3.3.1. Activation of p53 signaling in response to defects in ribosome production

Nucleolar stress is induced by either RNA Pol. I inhibition or
ribosome processing defects, and is characterized by an accumu-
lation of "free" RPs and AMFs that fail to be incorporated within
pre-ribosomal particles. The accumulation of these free proteins
drives the nucleolar stress response, in part through the activation
of p53 signaling (Fig. 5 and Table 1). Free RPL5/11/23 and RPS7
induce p53 activation by binding to and inhibiting MDM2. In
parallel, RPL26 increases p53 mRNA translation by binding to its
5'UTR. This translation activation is restrained by RPL26 ubiquiti-
nation by MDM2, thereby promoting its degradation [106]. The
AMF PAK1IP1 also contributes to p53 signaling activation by
interacting and partially inhibiting MDM2 activity [107].

An exhaustive study reported systematic changes in nucleolar
integrity after RNAi-mediated depletion of all individual RPs. This
screen revealed that RPLs seem more important than RPSs for
nucleolar morphology, the two major contributors to nucleolar
integrity being RPL5 and RPL11. In parallel, depletion of RPL5 or
RPL11 strongly prevents p53 stabilization. This is also the case for
several RPSs and only a few other RPLs [108]. Similar results were
obtained upon deletion of RPs in MCF7 and U2OS cells [109]. These
results indicate that, although the majority of RPLs are required for
nucleolar integrity, only a few of them function in p53 stabiliza-
tion. As depletion of most RPSs does not globally disrupt nucleolar
structure, further experiments are required to discriminate
whether their depletion does not cause p53 stabilization because
they are directly involved in stabilizing the protein or because
their absence does not induce a nucleolar stress response. Inter-
estingly, among the RPSs described in this study whose depletion
does not stabilize p53, haplo-insufficiency or knockdown of some
of them, such as RPS6/eS6, RPS14/uS11 and RPS19/eS19, has been
reported in other cell types to result in tissue-specific p53 stabi-
lization [109–111]. Therefore, the screen of Nicolas et al. unravels
connections between RPs, nucleolar integrity and p53 stabilization
that may not be applicable to all cell types [108]. The fact that RPS
<figure><img src="image_6.png" /><figcaption>**Fig. 5.** p53, a sensor and repressor of ribosome biogenesis</figcaption></figure>

This scheme represents the pathways leading to p53 stabilization upon nucleolar stress resulting from RNA Pol. I transcription or pre-rRNA processing defects in mammals. Black bubbles schematize the different ribosome biogenesis steps. Both defects induce the accumulation of free RPs and AMFs, among which some RPs (L23, S7), the 5S RNP (L5-L11-5S rRNA) and PAK1IP1 contribute to p53 stabilization by inhibiting the p53 ubiquitin ligase MDM2 that targets p53 for degradation under physiological conditions. In parallel, RPL26 increases p53 mRNA translation by binding to its 5'UTR. Upon stabilization, p53 activates the transcription by RNA Pol. II of genes involved in cell cycle arrest and cell fate decision. Activated p53 also impairs RNA Pol. I transcription initiation by interacting with TBP and TAF110 of the SL1 complex and preventing the UBF-SL1 association. It also downregulates RNA Pol. II-dependent expression of the exportin CRM1 and the importin IPO7, thereby interfering with the nucleo-cytoplasmic transport of RPs and AMFs, either "free" or within pre-ribosomal particles. The molecular interactions underlying repression of RNA Pol. III transcription by p53 and the genes targeted remain unclear. See the main text for more details.

or RPL contributions to nucleolar integrity or p53 levels appear to be tissue-/cell type-specific suggests that RPs establish tissue-specific interactions with other partners that would modulate their capacity to stabilize p53, an exciting research area so far poorly characterized.

Master regulators for p53 stabilization upon nucleolar stress are RPL5 and RPL11. They form a small complex with the 5S rRNA, referred to as the 5S RNP. This 5S RNP corresponds to the central protuberance on the mature 60S subunit, a domain essential for ribosome activity. During ribosome biogenesis, the 5S RNP is incorporated within pre-60S particles early in the maturation process, thanks to the AMFs BXDC1 and RRS1. Similarly to RPL5 and RPL11 depletion, the depletion of BXCD1 and RRS1 disrupts nucleolar integrity, which supports the crucial requirement of 5S RNP incorporation for nucleolar homeostasis [108]. Upon

ribosomal stress, or depletion of BXDC1 and RRS1, the 5S RNP accumulates in the nucleoplasm. This nucleoplasmic accumulation is responsible for MDM2 inhibition and p53 stabilization [109,112,113]. In addition, RPL5 and RPL11 are important for ARF-mediated p53 stabilization, as depletion of both proteins impairs this cellular response [112]. In contrast to other free RPs, which are mainly degraded by the proteasome upon nucleolar stress, RPL5 and RPL11 are protected from degradation within the 5S RNP. Upon actinomycin D treatment, which impairs RNA synthesis, newly translated RPL5 and RPL11 proteins are still imported into the nucleus where they maintain MDM2 repression [114]. The nuclear accumulation of the 5S RNP and p53 stabilization involve the NEDDylation of RPL11 by NEDD8. This post-translational modification may participate to 5S RNP stability and/or prevent its incorporation within pre-60S particles [113,115]. Recently, the SURF2 protein was introduced as a novel actor in the nucleolar stress response. SURF2 competes with MDM2 for binding to the 5S RNP and its overexpression, as observed in numerous cancer cell, prevents p53 activation in response to nucleolar stress [116].

### 3.3.2. A negative feedback loop of p53 on ribosome biogenesis

Once p53 is stabilized, one cellular response is to repress ribosome production (Fig. 5). p53 impairs RNA Pol. I transcription, in part by interacting with subunits TBP and TAF110 of the SL1 complex. These interactions prevent UBF-SL1 association, which is required to initiate rRNA synthesis [117,118]. The effect of p53 on RNA Pol. III transcription remains unclear. Indeed, three studies reported contradictory results concerning the targets of p53 among RNA Pol. III-transcribed genes. p53 is proposed to either globally repress the synthesis of all RNA Pol. III transcripts, or to repress Alu and U6 transcription but not that of 5S rRNA, 7SL, VAI, and tRNAs. Repression of RNA Pol. III machinery is thought to result from either p53-TBP and/or p53-TFIIIB interactions. TBP is important for the initiation of transcription by RNA Pol. II and III while TFIIIB directly interacts with the RNA Pol. III and is responsible for its recruitment to the transcription start sites (TSSs). Contradictory outcomes concerning the effect of p53 on RNA Pol. III activity may be due to the method used to prepare nuclear extracts or to the chromatin state of the DNA template. This suggests that in addition to p53 interaction with RNA Pol. III initiation machinery, the epigenetic landmarks modulates p53-mediated RNA Pol. III inhibition [119–121]. In some cancer cells, p53 loss is correlated with a loss of the equilibrium between 5S and 47S rDNA gene copy number. This loss results in an amplification of the 5S rDNA coupled with a reduction of 47S loci [122]. Therefore, the absence of p53 seems to impact rDNA integrity. We can postulate that by amplifying 5S rDNA, cells attempt to compensate for the loss of p53 by increasing the abundance of the 5S RNP.

In addition, p53 indirectly impairs the nucleo-cytoplasmic transport by downregulating the expression of the nuclear export protein CRM1 and the nuclear import protein/importin IPO7. These downregulations interfere with the nucleo-cytoplasmic transport of RPs and AMFs, either "free" or within pre-ribosomal particles [123,124]. In particular, the rapid accumulation of p53 after small ribosomal subunit synthesis inhibition correlates with a defect of pre-60S particle export and an impairment in the late stages of 5.8S rRNA processing [109]. p53 also negatively regulates ribosome biogenesis indirectly, either by inhibiting mTOR pathway and c-Myc, or by modulating ARF activity [125].

## 4. Concluding remarks

The dynamic regulation of ribosome biogenesis represents a central axis of cellular adaptation to both environmental and
intrinsic stress cues. This multifaceted regulation involves not only the global shutdown of transcription and translation, but also the selective translation of specific mRNAs through specialized ribosomes, as well as the activation of key stress-sensing pathways such as SAPK, AMPK, and p53. Together, these mechanisms act in concert to maintain cellular proteostasis, optimize energy utilization, and determine cell fate, i.e. promoting survival under manageable stress or triggering programmed cell death when homeostasis cannot be restored. Importantly, emerging research underscores the existence of cell-type and context-specific adaptations in ribosomal stress responses (Table 1), with profound implications for development, aging, and disease. Dysregulation of ribosome biogenesis is now recognized as a contributing factor in a variety of pathological conditions, including ribosomopathies and cancers, where aberrant stress signaling and impaired proteostasis drive disease progression. Therefore, unraveling the intricate interplay between stress signaling networks and ribosome biogenesis not only deepens our understanding of the molecular mechanisms governing cellular adaptation and homeostasis but also opens up novel avenues for innovative therapeutic strategies targeting stress-related disorders and malignancies.

### CRediT authorship contribution statement

**Emilie L. Cerezo:** Writing – review & editing, Writing – original draft, Investigation, Conceptualization. **Yves Henry:** Writing – review & editing. **Anthony K. Henras:** Writing – review & editing, Supervision, Project administration, Funding acquisition. **Yves Romeo:** Writing – review & editing, Supervision, Project administration, Funding acquisition.

### Funding

The Henry/Henras team is supported by collaborative research project (CRP) grants RIBOPRE60S, REA1COM and DUKKED from the "Agence Nationale de la Recherche" (to Y.H. and A.K.H.) and funding from "La Ligue Contre le Cancer" (to Y.R.). E.L.C. was supported by a Ph.D. fellowship from Toulouse University.

### Declaration of competing interest

We have no conflict of interest to declare.

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