Visualizing sequence-governed nucleotide selectivities and mutagenic consequences through a replicative cycle: processing of a bulky carcinogen N2-dG lesion in a Y-family DNA polymerase.

ABSTRACT: Understanding how DNA polymerases process lesions remains fundamental to determining the molecular origins of mutagenic translesion bypass. We have investigated how a benzo[a]pyrene-derived N(2)-dG adduct, 10S-(+)-trans-anti-[BP]-N(2)-dG ([BP]G*), is processed in Dpo4, the well-characterized Y-family bypass DNA polymerase. This polymerase has a slippage-prone spacious active site region. Experimental results in a 5'-C[BP]G*G-3' sequence context reveal significant selectivity for dGTP insertion that predominantly yields -1 deletion extension products. A less pronounced error-prone nonslippage pathway that leads to full extension products with insertion of A > C > G opposite the lesion is also observed. Molecular modeling and dynamics simulations follow the bypass of [BP]G* through an entire

SUBMITTER: Xu P 

PROVIDER: S-EPMC2929011 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature