Mechanism of Error‐Free Bypass of the Environmental Carcinogen N‐(2′‐Deoxyguanosin‐8‐yl)‐3‐aminobenzanthrone Adduct by Human DNA Polymerase η. (13th September 2016)

• Record Type: Journal Article
• Authors: Patra, Amritraj; Politica, Dustin A.; Chatterjee, Arindom; Tokarsky, E. John; Suo, Zucai; Basu, Ashis K.; Stone, Michael P.; Egli, Martin
• Is Part Of: Chembiochem. Volume 17:Number 21(2016)
• Page Start: 2033
• Page End: 2037
• Publication Date: 2016-09-13
• Subjects: DNA damage -- DNA polymerases -- environmental carcinogen -- lesion bypass -- nitrobenzanthrone -- X-ray crystallography; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201600420
• Languages: English
• ISSNs: 1439-4227

Abstract

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. Abstract : Mechanistic marvel : The environmental pollutant 3‐nitrobenzanthrone produces bulky aminobenzanthrone (ABA) DNA adducts that block replicative polymerases but can be bypassed in a largely error‐free manner by the human Y‐family polymerase η (hPol η). We report the crystallization of a ternary hPol η complex that provides crucial insight into the mechanism of error‐free bypass of this bulky lesion.