Impact of conformational heterogeneity of OxoG lesions and their pairing partners on bypass fidelity by Y family polymerases.

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 eta 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 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.

Polymerases:

Topics:

Structure and Structure/Function

Status:

new topics/pols set partial results complete validated

Results:

No results available for this paper.

Entry validated by:

Structures:

3GII 3GIK 3GIM 3GIJ 3GIL
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