## 4 Genomic Instability, Fe-S Clusters and Iron Chelators
### Iron Is Vital for DNA Replication and Repair  
DNA Helicases and Polymerases  
DNA helicases contain Fe-S clusters in the N terminus, essential in preserving DNA stability. DNA helicase enzymes include XPD, FANCJ, Dna2, Pud3, RTE and ChlR1 [81, 82]. XPD plays an integral part in nucleotide excision repair as a component of transcription factor II H (TFIIH) [83]. XPD catalyses the transcriptional site of DNA duplex opening at the transcriptional site damage or the site of DNA damage [84]. XPD contains a 4 Fe-4S cluster and is essential in genome maintenance through its role in nucleotide excision repair. Mutations in XPD cause trichothiocytrophy; this is due to mutated-XPD being unable to bind to single-stranded DNA and thus repair DNA by nucleotide excision repair [84]. FANCJ is a helicase that functions as a tumour suppressor caretaker and iron-containing protein: it contains a Fe-S cluster in a domain that has a vital role in regulating the enzyme. Additionally, it was indicated as a tumour suppressor caretaker as mutations were prevalent in breast cancer [85]. FANCJ is important in double-strand break repair by its direct interaction with BRCA1 through BRCT motifs; it also plays a role in homologous recombination and the Fanconi anaemia (FA) pathway of interstrand crosslink repair [86]. FANCJ helps to maintain chromatin structure and resolves G-quadruplex structures [87]. Mutations in FANCJ contribute to Fanconi anaemia, a disease where the patients are cancer-prone due to a hypersensitivity to agents that cause DNA crosslinks [88]. Further molecular studies are required to see the precise molecular functions of FANCJ. ChlR1 is a member of the FANCJ and XPD family and has a crucial 4 Fe-4S cluster [89]. Mutations in ChlR1 cause Warsaw Breakage syndrome, which leads to multiple abnormalities, this genetic instability syndrome predisposes people with this condition to cancer [90]. Recently, ChlR1 was shown to participate in DNA repair pathways. In a study where ChlR1/DDXII knockdown Hela cells were used with cisplatin, the Hela cells were highly sensitive to cisplatin [91]. Interestingly, cisplatin inhibits iron-responsive element-binding protein (IRP2), causing iron depletion similar to a chelator [92]. Studies also show ChlR1 role in normal sister chromatid cohesion [93]. Dna2 is an enzyme used in telomere maintenance, DNA double-strand break repair, Okazaki fragment processing, and cell cycle activation [94]. Dna2 also contains a 4 Fe-4S cluster essential for replication and repair [95]. Furthermore, it has been discovered in the mitochondria, where it participates in base excision repair (BER) [96]. Recently, the loss of the Fe-S cluster in Dna2 resulted in a change in conformation that caused it to impair DNA binding, which affected all its biochemical functions, such as its nuclease and helicase functions [97]. Additionally, iron transport and storage protein frataxin defects lead to BER defects. This suggests that the transportation and storage of iron from the labile iron pool are vital for DNA repair and replication enzymes such as Dna2 [98]. The helicases Dna2, FANCJ, ChlR1 and XPD have recently been discovered to have a Fe-S cluster and could be indirectly targeted by iron chelators that lower the available iron. The four DNA polymerases: Pol \(\alpha\), Pol \(\delta\), Pol \(\varepsilon\) and Pol \(\zeta\), require iron as a cofactor [99]. When DNA replicates, it starts with a primer; the DNA primase initiates an RNA primer before DNA Pol \(\alpha\) synthesises the leading strand; this additionally occurs at each Okazaki fragment. After roughly 20 nucleotides of DNA have been added by Pol \(\alpha\), the strand is recognised, facilitating the binding of proliferating cell nuclear antigen and the subsequent recruitment of Pol \(\delta\) and Pol \(\varepsilon\)[100]. Pol \(\delta\) completes every Okazaki fragment; thus, Pol \(\delta\) primarily works on the lagging strand [101]. Pol \(\varepsilon\) is principally used in the leading strand, whereas Pol \(\zeta\) is used when DNA is damaged [100].