Mechanistic Basis for the Bypass of a Bulky DNA Adduct Catalyzed by a Y-Family DNA Polymerase

Journal of the American Chemical Society
Rajan VyasZucai Suo

Abstract

1-Nitropyrene (1-NP), an environmental pollutant, induces DNA damage in vivo and is considered to be carcinogenic. The DNA adducts formed by the 1-NP metabolites stall replicative DNA polymerases but are presumably bypassed by error-prone Y-family DNA polymerases at the expense of replication fidelity and efficiency in vivo. Our running start assays confirmed that a site-specifically placed 8-(deoxyguanosin-N(2)-yl)-1-aminopyrene (dG(1,8)), one of the DNA adducts derived from 1-NP, can be bypassed by Sulfolobus solfataricus DNA polymerase IV (Dpo4), although this representative Y-family enzyme was paused strongly by the lesion. Pre-steady-state kinetic assays were employed to determine the low nucleotide incorporation fidelity and establish a minimal kinetic mechanism for the dG(1,8) bypass by Dpo4. To reveal a structural basis for dCTP incorporation opposite dG(1,8), we solved the crystal structures of the complexes of Dpo4 and DNA containing a templating dG(1,8) lesion in the absence or presence of dCTP. The Dpo4·DNA-dG(1,8) binary structure shows that the aminopyrene moiety of the lesion stacks against the primer/template junction pair, while its dG moiety projected into the cleft between the Finger and Little Finger domains...Continue Reading

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Citations

Oct 16, 2016·Chemical Research in Toxicology·A S Prakasha Gowda, Thomas E Spratt
Oct 15, 2020·The Journal of Biological Chemistry·Walter J Zahurancik, Zucai Suo
Jan 18, 2021·The Journal of Biological Chemistry·Walter J Zahurancik, Zucai Suo

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