Viewing Human DNA Polymerase β Faithfully and Unfaithfully Bypass an Oxidative Lesion by Time-Dependent Crystallography

Vyas, Rajan; Reed, Andrew J.; Tokarsky, E. John; Suo, Zucai

doi:10.1021/jacs.5b02109

Title: Viewing Human DNA Polymerase β Faithfully and Unfaithfully Bypass an Oxidative Lesion by Time-Dependent Crystallography

Journal Article · Tue Mar 31 00:00:00 EDT 2015 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/jacs.5b02109· OSTI ID:1186920

Vyas, Rajan ^[1]; Reed, Andrew J. ^[1]; Tokarsky, E. John ^[2]; Suo, Zucai ^[2]

The Ohio State Univ., Columbus, OH (United States). Dept of Chemistry and Biochemistry
The Ohio State Univ., Columbus, OH (United States). Dept of Chemistry and Biochemistry; The Ohio State Univ., Columbus, OH (United States). Biophysics Programs

One common oxidative DNA lesion, 8-oxo-7,8-dihydro-2'-deoxyguanine (8-oxoG), is highly mutagenic in vivo due to its anti-conformation forming a Watson–Crick base pair with correct deoxycytidine 5'-triphosphate (dCTP) and its syn-conformation forming a Hoogsteen base pair with incorrect deoxyadenosine 5'-triphosphate (dATP). Here in this article, we utilized time-resolved X-ray crystallography to follow 8-oxoG bypass by human DNA polymerase β (hPolβ). In the 12 solved structures, both Watson–Crick (anti-8-oxoG:anti-dCTP) and Hoogsteen (syn-8-oxoG:anti-dATP) base pairing were clearly visible and were maintained throughout the chemical reaction. Additionally, a third Mg²⁺ appeared during the process of phosphodiester bond formation and was located between the reacting α- and β-phosphates of the dNTP, suggesting its role in stabilizing reaction intermediates. After phosphodiester bond formation, hPolβ reopened its conformation, pyrophosphate was released, and the newly incorporated primer 3'-terminal nucleotide stacked, rather than base paired, with 8-oxoG. These structures provide the first real-time pictures, to our knowledge, of how a polymerase correctly and incorrectly bypasses a DNA lesion.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); National Science Foundation (NSF); USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357; MCB-0960961; ES009127; ES024585

OSTI ID:: 1186920

Journal Information:: Journal of the American Chemical Society, Vol. 137, Issue 15; ISSN 0002-7863

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 38 works

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