Modulators of DNA repair and damage responses p. 1 of 10 DNA Repair Modulators as Anticancer Agents

Summary: DNA damaging agents constitute a large fraction of the anticancer armamentarium (including radiation and small molecules). It is also becoming increasingly clear that DNA repair defects and defects in DNA damage response (DDR) cause cancer and are common in cancer cells. Those defects probably account for the selectivity of systemically administered anticancer agents toward cancer cells. Here, we summarize the DNA repair and DDR defects most commonly associated with human cancer. We also summarize the various DNA repair pathways elicited by the anticancer agents, and the inhibitors currently available to interfere with those pathways. Finally, we discuss the rationale approaches for using DNA repair and DDR inhibitors based on the specific tumor defects (conditional/synthetic lethality), and examples for rational development of combination therapies. Abbreviations and glossary (in alphabetic order): AGT: O6-alkylguanine transferase (polypeptide which transfers O6 alkyl guanine adducts to itself); AT: ataxia telangiectasia (a rare genetic disease with cancer predisposition); ATM: ataxia telangiectasia mutated (the gene mutated in AT; it encodes a PIKK); AP site: apyrimidinic/apurinic site; BER: base excisio