Impact of Conformational Heterogeneity of OxoG Lesions and Their Pairing Partners on Bypass Fidelity by Y Family Polymerases
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 {eta} preferentially extend from the oxoG{center_dot}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){center_dot}C and oxoG{center_dot}A pairs. However, the latter manifest conformational heterogeneity, adopting both oxoG(syn){center_dot}A(anti) and oxoG(anti){center_dot}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 {eta}, such a dynamic screening mechanism might be utilized by Dpo4 and Pol {eta} to regulate error-free versus error-prone bypass of oxoG and other lesions.
- Research Organization:
- Argonne National Laboratory (ANL)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1005668
- Journal Information:
- Structure, Journal Name: Structure Journal Issue: (5) ; 05, 2009 Vol. 17
- Country of Publication:
- United States
- Language:
- ENGLISH
Similar Records
Structural Basis for Error-free Replication of Oxidatively Damaged DNA by Yeast DNA Polymerase eta
Structural basis of DNA synthesis opposite 8-oxoguanine by human PrimPol primase-polymerase