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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Olga Rechkoblit & Alexander Kolbanovskiy & Hannah Landes & Nicholas E. Geacintov & Aneel K. Aggarwal, 2017. "Mechanism of error-free replication across benzo[a]pyrene stereoisomers by Rev1 DNA polymerase," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01013-5
    DOI: 10.1038/s41467-017-01013-5
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    Cited by:

    1. Tyler M. Weaver & Timothy H. Click & Thu H. Khoang & M. Todd Washington & Pratul K. Agarwal & Bret D. Freudenthal, 2022. "Mechanism of nucleotide discrimination by the translesion synthesis polymerase Rev1," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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