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Chembiochem. 2016 Nov 3;17(21):2033-2037. doi: 10.1002/cbic.201600420. Epub 2016 Sep 13.

Mechanism of Error-Free Bypass of the Environmental Carcinogen N-(2'-Deoxyguanosin-8-yl)-3-aminobenzanthrone Adduct by Human DNA Polymerase η.

Author information

1
Department of Biochemistry, Vanderbilt University, School of Medicine, 868A Robinson Research Building, Nashville, TN, 37232, USA.
2
Department of Chemistry, Vanderbilt University, College of Arts & Science, Station B, Box 1822, Nashville, TN, 37235, USA.
3
Department of Chemistry, University of Connecticut, 55 North Eagleville Rd, Storrs, CT, 06269, USA.
4
Department of Chemistry and Biochemistry, Ohio State University, 484 West 12th Avenue, Columbus, OH, 43210, USA.
5
Department of Chemistry, Vanderbilt University, College of Arts & Science, Station B, Box 1822, Nashville, TN, 37235, USA. michael.p.stone@vanderbilt.edu.
6
Department of Biochemistry, Vanderbilt University, School of Medicine, 868A Robinson Research Building, Nashville, TN, 37232, USA. martin.egli@vanderbilt.edu.

Abstract

The environmental pollutant 3-nitrobenzanthrone produces bulky aminobenzanthrone (ABA) DNA adducts with both guanine and adenine nucleobases. A major product occurs at the C8 position of guanine (C8-dG-ABA). These adducts present a strong block to replicative polymerases but, remarkably, can be bypassed in a largely error-free manner by the human Y-family polymerase η (hPol η). Here, we report the crystal structure of a ternary Pol⋅DNA⋅dCTP complex between a C8-dG-ABA-containing template:primer duplex and hPol η. The complex was captured at the insertion stage and provides crucial insight into the mechanism of error-free bypass of this bulky lesion. Specifically, bypass involves accommodation of the ABA moiety inside a hydrophobic cleft to the side of the enzyme active site and formation of an intra-nucleotide hydrogen bond between the phosphate and ABA amino moiety, allowing the adducted guanine to form a standard Watson-Crick pair with the incoming dCTP.

KEYWORDS:

DNA damage; DNA polymerases; X-ray crystallography; environmental carcinogen; lesion bypass; nitrobenzanthrone

PMID:
27556902
PMCID:
PMC5172388
DOI:
10.1002/cbic.201600420
[Indexed for MEDLINE]
Free PMC Article

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