Uncovering a unique approach for damaged DNA replication: A computational investigation of a mutagenic tobacco-derived thymine lesion.

ABSTRACT: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent nicotine carcinogen that leads to many DNA lesions, the most persistent being the O2-[4-oxo-4-(3-pyridyl)butyl]thymine adduct (POB-T). Although the experimental mutagenic profile for the minor groove POB-T lesion has been previously reported, the findings are puzzling in terms of the human polymerases involved. Specifically, while pol κ typically replicates minor groove adducts, in vivo studies indicate pol η replicates POB-T despite being known for processing major groove adducts. Our multiscale modeling approach reveals that the canonical (anti) glycosidic orientation of POB-T can fit in the pol κ active site, but only a unique (syn) POB-T conformation is accommodated by pol η. These distinct binding orientations rationalize the

SUBMITTER: Wilson KA 

PROVIDER: S-EPMC6393286 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature