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 journalArticle

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

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Base Pairing
DNA Damage
Catalytic Domain
7,8-dihydro-8-oxoguanine

Keywords

  • DNA
  • PROTEINS

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Impact of Conformational Heterogeneity of OxoG Lesions and Their Pairing Partners on Bypass Fidelity by Y Family Polymerases. / Rechkoblit, Olga; Malinina, Lucy; Cheng, Yuan; Geacintov, Nicholas E.; Broyde, Suse; Patel, Dinshaw J.

In: Structure, Vol. 17, No. 5, 13.05.2009, p. 725-736.

Research output: Contribution to journalArticle

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AU - Patel, Dinshaw J.

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