Differing conformational pathways before and after chemistry for insertion of dATP versus dCTP opposite 8-OxoG in DNA polymerase β

Yanli Wang, Sujatha Reddy, William A. Beard, Samuel H. Wilson, Tamar Schlick

Research output: Contribution to journalArticlepeer-review

Abstract

To elucidate how human DNA polymerase β (pol β) discriminates dATP from dCTP when processing 8-oxoguanine (8-oxoG), we analyze a series of dynamics simulations before and after the chemical step with dATP and dCTP opposite an 8-oxoG template started from partially open complexes of pol β. Analyses reveal that the thumb closing of pol β before chemistry is hampered when the incorrect nucleotide dATP is bound opposite 8-oxoG; the unfavorable interaction between active-site residue Tyr271 and dATP that causes an anti to syn change in the 8-oxoG (syn):dATP complex explains this slow motion, in contrast to the 8-oxoG (anti ):dCTP system. Such differences in conformational pathways before chemistry for mismatched versus matched complexes help explain the preference for correct insertion across 8-oxoG by pol β. Together with reference studies with a nonlesioned G template, we propose that 8-oxoG leads to lower efficiency in pol β's incorporation of dCTP compared with G by affecting the requisite active-site geometry for the chemical reaction before chemistry. Furthermore, because the active site is far from ready for the chemical reaction after partial closing or even full thumb closing, we suggest that pol β is tightly controlled not only by the chemical step but also by a closely related requirement for subtle active-site rearrangements after thumb movement but before chemistry.

Original languageEnglish (US)
Pages (from-to)3063-3070
Number of pages8
JournalBiophysical journal
Volume92
Issue number9
DOIs
StatePublished - May 2007

ASJC Scopus subject areas

  • Biophysics

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