Impact of Conformational Heterogeneity of OxoG Lesions and Their Pairing Partners on Bypass Fidelity by Y Family Polymerases

Olga Rechkoblit, Lucy Malinina, Yuan Cheng, Nicholas E. Geacintov, Suse Broyde, Dinshaw J. Patel

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

7,8-Dihydro-8-oxoguanine (oxoG), the predominant oxidative DNA damage lesion, is processed differently by high-fidelity and Y-family lesion bypass polymerases. Although high-fidelity polymerases extend predominantly from an A base opposite an oxoG, the Y-family polymerases Dpo4 and human Pol η preferentially extend from the oxoG•C base pair. We have determined crystal structures of extension Dpo4 ternary complexes with oxoG opposite C, A, G, or T and the next nascent base pair. We demonstrate that neither template backbone nor the architecture of the active site is perturbed by the oxoG(anti)•C and oxoG•A pairs. However, the latter manifest conformational heterogeneity, adopting both oxoG(syn)•A(anti) and oxoG(anti)•A(syn) alignment. Hence, the observed reduced primer extension from the dynamically flexible 3′-terminal primer base A is explained. Because of homology between Dpo4 and Pol η, such a dynamic screening mechanism might be utilized by Dpo4 and Pol η to regulate error-free versus error-prone bypass of oxoG and other lesions.

Original languageEnglish (US)
Pages (from-to)725-736
Number of pages12
JournalStructure
Volume17
Issue number5
DOIs
StatePublished - May 13 2009

Bibliographical note

Funding Information:
The research was supported by National Institutes of Health grants CA46533 to D.J.P, CA75449 to S.B., CA99194 to N.E.G and Ruth L. Kirschstein National Research Service Award F32 GM069152 to O.R. Partial support for computational infrastructure and computer systems management was also provided to S.B. by CA28038. We would like to thank the staff at the Northeastern Collaborative Access Team beamlines of the Advance Photon Source (APS), Argonne National Laboratory, supported by award RR-15301 from the National Center for Research Resources at the National Institute of Health, for assistance with data collection. Use of the Advanced Photon Source is supported by the U.S. Department of Energy, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Keywords

  • DNA
  • PROTEINS

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