Involvement of translesion synthesis DNA polymerases in DNA interstrand crosslink repair.
DNA interstrand crosslinks (ICLs) covalently join the two strands of a DNA duplex and block essential processes such as DNA replication and transcription. Several important anti-tumor drugs such as cisplatin and nitrogen mustards exert their cytotoxicity by forming ICLs. However, multiple complex pathways repair ICLs and these are thought to contribute to the development of resistance towards ICL-inducing agents. While the understanding of many aspects of ICL repair is still rudimentary, studies in recent years have provided significant insights into the pathways of ICL repair. In this perspective we review the recent advances made in elucidating the mechanisms of ICL repair with a focus on the role of TLS polymerases. We describe the emerging models for how these enzymes contribute to and are regulated in ICL repair, discuss the key open questions and examine the implications for this pathway in anti-cancer therapy.
Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
Upasana
U
Roy
Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794-3400, USA. Electronic address: orlando.scharer@stonybrook.edu.
Orlando D
OD
Schärer
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D003432:Cross-Linking Reagents / Q000627:therapeutic use; D004247:DNA / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008466:Mechlorethamine / Q000627:therapeutic use; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D014158:Transcription, Genetic / Q000187:drug effects; D014981:Xenopus
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D008466:Mechlorethamine; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D002945:Cisplatin
Cisplatin; DNA polymerases; Inter-strand crosslink repair; Nitrogen mustard; Translesion synthesis