title: Structural basis of human DNA polymerase η-mediated chemoresistance to cisplatin.
abstract: Cisplatin (cis-diamminedichloroplatinum) and related compounds cause DNA damage and are widely used as anticancer agents. Chemoresistance to cisplatin treatment is due in part to translesion synthesis by human DNA polymerase η (hPol η). Here, we report crystal structures of hPol η complexed with intrastrand cisplatin-1,2-cross-linked DNA, representing four consecutive steps in translesion synthesis. In contrast to the generally enlarged and nondiscriminating active site of Y-family polymerases like Dpo4, Pol η is specialized for efficient bypass of UV-cross-linked pyrimidine dimers. Human Pol η differs from the yeast homolog in its binding of DNA template. To incorporate deoxycytidine opposite cisplatin-cross-linked guanines, hPol η undergoes a specific backbone rearrangement to accommodate the larger base dimer and minimizes the DNA distortion around the lesion. Our structural analyses show why Pol η is inefficient at extending primers after cisplatin lesions, which necessitates a second translesion DNA polymerase to complete bypass in vivo. A hydrophobic pocket near the primer-binding site in human Pol η is identified as a potential drug target for inhibiting translesion synthesis and, thereby, reducing chemoresistance.
authors.affiliation: Institute of Nuclear-Agricultural Sciences,  Zhejiang University, Hangzhou 310029,  China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhao
authors.forename: Christian
authors.initials: C
authors.lastname: Biertümpfel
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gregory
authors.forename: Yue-Jin
authors.initials: YJ
authors.lastname: Hua
authors.forename: Fumio
authors.initials: F
authors.lastname: Hanaoka
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D009690:Nucleic Acid Conformation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011740:Pyrimidine Dimers / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D000099270:Y-Family DNA Polymerases
chemical_list: D000255:Adenosine Triphosphate; D002945:Cisplatin; D003432:Cross-Linking Reagents; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D011740:Pyrimidine Dimers; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases