## 4 Genomic Instability, Fe-S Clusters and Iron Chelators
### Could Iron chelators Passively or Actively Target Fe-S Clusters  
Iron is crucial for maintaining genomic stability in DNA polymerases and helicases through the Fe-S cluster and thus in DNA replication and repair. It therefore makes sense that loss of chelate-able iron via iron chelators could limit the iron available for Fe-S clusters. Iron chelators have been shown to remove iron from the labile cytosolic iron pool and the mitochondrial labile iron pool, supplying iron to Fe-S clusters. As a result, it is logical that chelating iron would limit the iron available for DNA replication and repair. It is not fully understood to what degree iron chelators could remove iron from Fe-S clusters. Chelators usually work on the cheatable iron pool; however, the IRP sensor is an example of the removal of iron from Fe-S clusters. In iron-deficient conditions, IRP1 does not have enough iron to form a full [4 Fe-4S], creating a [3 Fe-4S] cluster instead. This degrades to the apo-protein of IRP1, which binds to IRE to produce more iron [52,149]. Further, the recent discovery that scaffold proteins such as ISU enable labile Fe -S clusters to form before incorporation into proteins raises many questions. Can iron chelators interfere with this pathway and potentially further limit Fe-S clusters' role in the DNA damage response? Currently, it is unknown and unlikely that iron chelators can directly interact with Fe-S clusters. However, it has been shown that Fe-S clusters incorporated into proteins, such as ribonucleotide reductase, can be inhibited by iron chelators that remove iron from the labile iron pool and lower the supply of iron into these proteins [110]. Fe-S clusters have inherent susceptibility to oxidation, which makes Fe-S targets for activation by ROS. This further mechanism iron chelators can be designed to target Fe-S clusters by designing chelators that can increase ROS. Fe-S susceptibility to ROS was first seen in antibiotics, where quinolones increase the NAD+/NADH ratio resulting in ROS production and Fe-S cluster disruption [150,151, 152]. This is thought to be because the superoxide anion (O2*-) and hydrogen peroxide can inactivate Fe-S clusters [153]. Since then, drugs that induced ROS, such as \(\beta\)-Phenethyl isothiocyanate (PEITC), were used to target Fe-S centres, specifically the NADH dehydrogenase Fe-S protein-3, which resulted in its degradation by lowering the mitochondrial respiration and mitochondrial glutathione [154]. However, the drug hydroxyurea is known to chelate iron, remove it from the labile iron pool, and inhibit RnR; it has been shown to target Fe-S clusters by inducing ROS [155,156]. It was postulated that the hydroxyurea effect could also be because it scavenges tyrosyl radicals in Fe-S biosynthesis [156]. Recently DFO (deferoxamine) has been altered so that it targets the mitochondria by the addition of a triphenylphosphonium group [157]. This resulted in the new complex, mitoDFO, accumulating in the mitochondria and lowering Fe-S cluster biogenesis. The diminished Fe-S cluster biogenesis consequently resulted in a decrease in the activity of the resulting Fe-S proteins. MitoDFO showed a 40-fold increase in antiproliferative of cancer cells. This is one of the first studies to examine how iron chelators targeted to the mitochondria can affect Fe-S clusters. This is an evolving field; iron's crucial role in genomic stability is well-defined when referring to RnR; however, little is known about the effect that chelators or iron deficiency has on Fe-S clusters and nuclei acid metabolism [158]. It is established that the overexpression of key Fe-S clusters promotes tumorigenesis, and mutations in the DNA repair enzymes can cause cancer [79]. The susceptibility of these proteins to ROS raises whether iron chelators that are known to induce ROS and limit the labile iron pool could potentially target Fe-S centres in cancer.