Mutagenic Replication of the Major Oxidative Adenine Lesion 7,8-Dihydro-8-oxoadenine by Human DNA Polymerases

Journal of the American Chemical Society
Myong-Chul KoagSeongmin Lee

Abstract

Reactive oxygen species attack DNA to produce 7,8-dihyro-8-oxoguanine (oxoG) and 7,8-dihydro-8-oxoadenine (oxoA) as major lesions. The structural basis for the mutagenicity of oxoG, which induces G to T mutations, is well understood. However, the structural basis for the mutagenic potential of oxoA, which induces A to C mutations, remains poorly understood. To gain insight into oxoA-induced mutagenesis, we conducted kinetic studies of human DNA polymerases β and η replicating across oxoA and structural studies of polβ incorporating dTTP/dGTP opposite oxoA. While polη readily bypassed oxoA, it incorporated dGTP opposite oxoA with a catalytic specificity comparable to that of correct insertion, underscoring the promutagenic nature of the major oxidative adenine lesion. Polη and polβ incorporated dGTP opposite oxoA ∼170-fold and ∼100-fold more efficiently than that opposite dA, respectively, indicating that the 8-oxo moiety greatly facilitated error-prone replication. Crystal structures of polβ showed that, when paired with an incoming dTTP, the templating oxoA adopted an anti conformation and formed Watson-Crick base pair. When paired with dGTP, oxoA adopted a syn conformation and formed a Hoogsteen base pair with Watson-Crick-li...Continue Reading

References

Sep 7, 1992·FEBS Letters·R OlinskiM Dizdaroglu
Apr 25, 1991·Nucleic Acids Research·W GuschlbauerG V Fazakerley
Jan 1, 1991·Annual Review of Biochemistry·H Echols, M F Goodman
Apr 1, 1987·Mutation Research·L C SowersW D Sedwick
Jun 6, 1995·Proceedings of the National Academy of Sciences of the United States of America·J S HoffmannG Villani
Jul 1, 1993·Trends in Genetics : TIG·A P Grollman, M Moriya
Apr 15, 1996·Nucleic Acids Research·P Jaruga, M Dizdaroglu
Oct 15, 1998·Proceedings of the National Academy of Sciences of the United States of America·Y CanitrotJ S Hoffmann
Mar 14, 2000·The Journal of Biological Chemistry·F YuanZ Wang
Sep 7, 2000·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Y CanitrotC Cazaux
Nov 1, 2000·Proceedings of the National Academy of Sciences of the United States of America·D C MalinsM A Vinson
Feb 6, 2002·Journal of Molecular Biology·Laurence ServantJean-Sébastien Hoffmann
Oct 22, 2002·The Journal of Biological Chemistry·Laurence ServantJean-Sébastien Hoffmann
Feb 28, 2004·The Journal of Biological Chemistry·Thomas A Kunkel
May 18, 2004·The Journal of Biological Chemistry·William A BeardSamuel H Wilson
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Apr 18, 2006·Structure·Vinod K BatraSamuel H Wilson
Oct 27, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Agata CopaniFerdinando Nicoletti
Apr 25, 2007·Nucleic Acids Research·Ian W DavisDavid C Richardson

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Citations

Feb 11, 2020·The Biochemical Journal·Hala Ouzon-ShubeitaSeongmin Lee
Apr 14, 2020·Nucleic Acids Research·Myong-Chul KoagSeongmin Lee
Oct 22, 2020·Nature Communications·Samantha L SanfordPatricia L Opresko
Apr 22, 2021·The Biochemical Journal·Hunmin Jung, Seongmin Lee
Jul 21, 2020·The Biochemical Journal·Hunmin Jung, Seongmin Lee

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