Computational insights into the mutagenicity of two tobacco-derived carcinogenic DNA lesions.

ABSTRACT: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent carcinogen found in all tobacco products that leads to a variety of DNA lesions in cells, including O6-[4-oxo-4-(3-pyridyl)butyl]guanine (POB-G) and O6-[4-hydroxy-4-(3-pyridyl)butyl]guanine (PHB-G), which differ by only a single substituent in the bulky moiety. This work uses a multiscale computational approach to shed light on the intrinsic conformational and base-pairing preferences of POB-G and PHB-G, and the corresponding properties in DNA and the polymerase η active site. Our calculations reveal that both lesions form stable pairs with C and T, with the T pairs being the least distorted relative to canonical DNA. This rationalizes the experimentally reported mutational profile for POB-G and validates our computational model. T

SUBMITTER: Wilson KA 

PROVIDER: S-EPMC6294509 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature