title: Structural basis for cisplatin DNA damage tolerance by human polymerase η during cancer chemotherapy.
abstract: A major clinical problem in the use of cisplatin to treat cancers is tumor resistance. DNA polymerase η (Pol-η) is a crucial polymerase that allows cancer cells to cope with the cisplatin-DNA adducts that are formed during chemotherapy. We present here a structure of human Pol-η inserting deoxycytidine triphosphate (dCTP) opposite a cisplatin intrastrand cross-link (PtGpG). We show that the specificity of human Pol-η for PtGpG derives from an active site that is open to permit Watson-Crick geometry of the nascent PtGpG-dCTP base pair and to accommodate the lesion without steric hindrance. This specificity is augmented by the residues Gln38 and Ser62, which interact with PtGpG, and Arg61, which interacts with the incoming dCTP. Collectively, the structure provides a basis for understanding how Pol-η in human cells can tolerate the DNA damage caused by cisplatin chemotherapy and offers a framework for the design of inhibitors in cancer therapy.
authors.affiliation: Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Ummat
authors.forename: Olga
authors.initials: O
authors.lastname: Rechkoblit
authors.forename: Rinku
authors.initials: R
authors.lastname: Jain
authors.forename: Jayati
authors.initials: J
authors.lastname: Roy Choudhury
authors.forename: Robert E
authors.initials: RE
authors.lastname: Johnson
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Silverstein
authors.forename: Angeliki
authors.initials: A
authors.lastname: Buku
authors.forename: Samer
authors.initials: S
authors.lastname: Lone
authors.forename: Louise
authors.initials: L
authors.lastname: Prakash
authors.forename: Satya
authors.initials: S
authors.lastname: Prakash
authors.forename: Aneel K
authors.initials: AK
authors.lastname: Aggarwal
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D020134:Catalytic Domain; D002945:Cisplatin / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D018736:DNA Adducts / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry* / Q000378:metabolism*; D003845:Deoxycytosine Nucleotides / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D013379:Substrate Specificity; D000099270:Y-Family DNA Polymerases
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D018736:DNA Adducts; D004259:DNA-Directed DNA Polymerase; D003845:Deoxycytosine Nucleotides; C057270:cisplatin-DNA adduct; C024107:2'-deoxycytidine 5'-triphosphate; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases