title: Mechanism of Error-Free Bypass of the Environmental Carcinogen N-(2'-Deoxyguanosin-8-yl)-3-aminobenzanthrone Adduct by Human DNA Polymerase η.
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.
authors.affiliation: Department of Biochemistry, Vanderbilt University, School of Medicine, 868A Robinson Research Building, Nashville, TN, 37232, USA.
authors.forename: Amritraj
authors.initials: A
authors.lastname: Patra
authors.affiliation: Department of Chemistry, Vanderbilt University, College of Arts & Science, Station B, Box 1822, Nashville, TN, 37235, USA.
authors.forename: Dustin A
authors.initials: DA
authors.lastname: Politica
authors.affiliation: Department of Chemistry, University of Connecticut, 55 North Eagleville Rd, Storrs, CT, 06269, USA.
authors.forename: Arindom
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Department of Chemistry and Biochemistry, Ohio State University, 484 West 12th Avenue, Columbus, OH, 43210, USA.
authors.forename: E John
authors.initials: EJ
authors.lastname: Tokarsky
authors.affiliation: Department of Chemistry and Biochemistry, Ohio State University, 484 West 12th Avenue, Columbus, OH, 43210, USA.
authors.forename: Zucai
authors.initials: Z
authors.lastname: Suo
authors.affiliation: Department of Chemistry, University of Connecticut, 55 North Eagleville Rd, Storrs, CT, 06269, USA.
authors.forename: Ashis K
authors.initials: AK
authors.lastname: Basu
authors.affiliation: Department of Chemistry, Vanderbilt University, College of Arts & Science, Station B, Box 1822, Nashville, TN, 37235, USA. michael.p.stone@vanderbilt.edu.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Stone
authors.affiliation: Department of Biochemistry, Vanderbilt University, School of Medicine, 868A Robinson Research Building, Nashville, TN, 37232, USA. martin.egli@vanderbilt.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Egli
mesh_terms: D001551:Benz(a)Anthracenes / Q000737:chemistry / Q000378:metabolism*; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D000099270:Y-Family DNA Polymerases
chemical_list: D001551:Benz(a)Anthracenes; D018736:DNA Adducts; D004259:DNA-Directed DNA Polymerase; D003849:Deoxyguanosine; C000622103:N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases
keywords: DNA damage; DNA polymerases; X-ray crystallography; environmental carcinogen; lesion bypass; nitrobenzanthrone