DNA helicases involved in DNA repair and their roles in cancer

Abstract

Helicase-dependent DNA damage response and repair mechanisms help cells to cope with endogenous or exogenous stress to prevent chromosomal instability and maintain cellular homeostasis. Inactivating mutations in DNA helicase genes are linked to genetic disorders that are frequently associated with various cancers. However, the expression of many DNA helicases is upregulated in transformed or neoplastic cells and tissues and is required for cancer cell proliferation or resistance to DNA damage imposed by chemotherapies. The RecQ and iron-sulphur (Fe-S) families of DNA helicases have prominent roles in the maintenance of genomic stability through their catalytic functions and protein interactions in telomere maintenance and DNA repair pathways including nucleotide-excision repair (NER), homologous recombination (HR)-mediated repair of double-strand breaks (DSBs), interstrand crosslink (ICL) repair, and base-excision repair (BER). Specialized DNA helicases efficiently unwind G-quadruplex (G4) DNA and other forms of alternative DNA structures such as telomeric displacement loops (T-loops). Emerging evidence suggests that DNA helicases that unwind non-conventional DNA structures have important roles in the replication or repair of telomeres. Replication forks in rapidly dividing cancer cells are likely to encounter DNA lesions that perturb fork progression. Evidence suggests that certain DNA helicases help cells to cope with replicative lesions by remodelling the fork, restoring the integrity of broken replication forks, or having a role in the signalling mechanism for the intra-S-phase checkpoint. Elevated expression of DNA helicases in rapidly proliferating cells and tumours suggests that they have a role in resistance to DNA-damaging agents and may represent good biomarkers for response to chemotherapies. High-throughput screening of chemical libraries may prove to be beneficial for the discovery of small molecules that modulate helicase function in vivo. Such compounds may be useful in synthetic lethal approaches used in anticancer strategies that target tumours with existing DNA repair deficiencies.