Mechanism of error-free replication across benzo[a]pyrene stereoisomers by Rev1 DNA polymerase

Olga Rechkoblit (), Alexander Kolbanovskiy, Hannah Landes, Nicholas E. Geacintov and Aneel K. Aggarwal
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Olga Rechkoblit: Icahn School of Medicine at Mount Sinai
Alexander Kolbanovskiy: New York University
Hannah Landes: Icahn School of Medicine at Mount Sinai
Nicholas E. Geacintov: New York University
Aneel K. Aggarwal: Icahn School of Medicine at Mount Sinai

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract Benzo[a]pyrene (BP) is a carcinogen in cigarette smoke which, after metabolic activation, can react with the exocyclic N 2 amino group of guanine to generate four stereoisomeric BP-N 2-dG adducts. Rev1 is unique among translesion synthesis DNA polymerases in employing a protein-template-directed mechanism of DNA synthesis opposite undamaged and damaged guanine. Here we report high-resolution structures of yeast Rev1 with three BP-N 2-dG adducts, namely the 10S (+)-trans-BP-N 2-dG, 10R (+)-cis-BP-N 2-dG, and 10S ( − )-cis-BP-N 2-dG. Surprisingly, in all three structures, the bulky and hydrophobic BP pyrenyl residue is entirely solvent-exposed in the major groove of the DNA. This is very different from the adduct alignments hitherto observed in free or protein-bound DNA. All complexes are well poised for dCTP insertion. Our structures provide a view of cis-BP-N 2-dG adducts in a DNA polymerase active site, and offer a basis for understanding error-free replication of the BP-derived stereoisomeric guanine adducts.

Date: 2017
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DOI: 10.1038/s41467-017-01013-5

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