title: Structure-dependent bypass of DNA interstrand crosslinks by translesion synthesis polymerases.
abstract: DNA interstrand crosslinks (ICLs), inhibit DNA metabolism by covalently linking two strands of DNA and are formed by antitumor agents such as cisplatin and nitrogen mustards. Multiple complex repair pathways of ICLs exist in humans that share translesion synthesis (TLS) past a partially processed ICL as a common step. We have generated site-specific major groove ICLs and studied the ability of Y-family polymerases and Pol ζ to bypass ICLs that induce different degrees of distortion in DNA. Two main factors influenced the efficiency of ICL bypass: the length of the dsDNA flanking the ICL and the length of the crosslink bridging two bases. Our study shows that ICLs can readily be bypassed by TLS polymerases if they are appropriately processed and that the structure of the ICL influences which polymerases are able to read through it.
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: The Vinh
authors.initials: TV
authors.lastname: Ho
authors.forename: Angelo
authors.initials: A
authors.lastname: Guainazzi
authors.forename: Semsi Burak
authors.initials: SB
authors.lastname: Derkunt
authors.forename: Milica
authors.initials: M
authors.lastname: Enoiu
authors.forename: Orlando D
authors.initials: OD
authors.lastname: Schärer
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity; D002945:Cisplatin / Q000633:toxicity; D003432:Cross-Linking Reagents / Q000633:toxicity; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D008466:Mechlorethamine / Q000633:toxicity; D009690:Nucleic Acid Conformation; D009713:Nucleotidyltransferases / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013698:Templates, Genetic; D000099270:Y-Family DNA Polymerases
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D003432:Cross-Linking Reagents; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D003845:Deoxycytosine Nucleotides; D008466:Mechlorethamine; D009713:Nucleotidyltransferases; D029701:Saccharomyces cerevisiae Proteins; C024107:2'-deoxycytidine 5'-triphosphate; C425929:DNA polymerase zeta; C100951:REV1 protein, S cerevisiae; D000099270:Y-Family DNA Polymerases