Impact of Conformational Heterogeneity of OxoG Lesions and Their Pairing Partners on Bypass Fidelity by Y Family Polymerases Journal Article
| Authors: | Rechkoblit, O.; Malinina, L.; Cheng, Y.; Geacintov, N. E.; Broyde, S.; Patel, D. J. |
| Article Title: | 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 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. © 2009 Elsevier Ltd. All rights reserved. |
| Keywords: | unclassified drug; dna polymerase; protein conformation; proteins; dna damage; dna repair; dna; molecular sequence data; guanine; screening; base sequence; base pairing; crystal structure; crystallography, x-ray; binding sites; conformation; nucleic acid conformation; sequence homology; protein family; protein derivative; error; enzyme active site; 8 hydroxyguanine; dpo4 protein; dna polymerase beta |
| Journal Title: | Structure |
| Volume: | 17 |
| Issue: | 5 |
| ISSN: | 0969-2126 |
| Publisher: | Cell Press |
| Date Published: | 2009-05-13 |
| Start Page: | 725 |
| End Page: | 736 |
| Language: | English |
| DOI: | 10.1016/j.str.2009.03.011 |
| PUBMED: | 19446528 |
| PROVIDER: | scopus |
| PMCID: | PMC4193663 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 30 November 2010" - "CODEN: STRUE" - "Source: Scopus" |
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