Document Type
Article
Publication Date
11-5-2009
Description
The 5R thymine glycol (5R-Tg) DNA lesion exists as a mixture of cis-(5R,6S) and trans-(5R,6R) epimers; these modulate base excision repair. We examine the 7:3 cis-(5R,6S):trans-(5R,6R) mixture of epimers paired opposite adenine in the 5′-GTgG-3′ sequence with regard to nucleotide excision repair. Human XPA recognizes the lesion comparably to the C8-dG acetylaminoflourene (AAF) adduct, whereas XPC/HR23B recognition of Tg is superior. 5R-Tg is processed by the Escherichia coli UvrA and UvrABC proteins less efficiently than the C8-dG AAF adduct. For the cis-(5R,6S) epimer Tg and A are inserted into the helix, remaining in the Watson-Crick alignment. The Tg N3H imine and A N6 amine protons undergo increased solvent exchange. Stacking between Tg and the 3′-neighbor G•C base pair is disrupted. The solvent accessible surface and T2 relaxation of Tg increases. Molecular dynamics calculations predict that the axial conformation of the Tg CH3 group is favored; propeller twisting of the Tg•A pair and hydrogen bonding between Tg OH6 and the N7 atom of the 3′-neighbor guanine alleviate steric clash with the 5′-neighbor base pair. Tg also destabilizes the 5′-neighbor G•C base pair. This may facilitate flipping both base pairs from the helix, enabling XPC/HR23B recognition prior to recruitment of XPA.
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This work is licensed under a Creative Commons Attribution-Noncommercial 3.0 License
Citation Information
Brown, Kyle L.; Roginskaya, Marina; Zou, Yue; Altamirano, Alvin; Basu, Ashis K.; and Stone, Michael P.. 2009. Binding of the Human Nucleotide Excision Repair Proteins XPA and XPC/HR23B to the 5R-Thymine Glycol Lesion and Structure of the cis-(5R,6S) Thymine Glycol Epimer in the 5′-GTgG-3′ Sequence: Destabilization of Two Base Pairs at the Lesion Site. Nucleic Acids Research. Vol.38(2). 428-440. https://doi.org/10.1093/nar/gkp844 PMID: 19892827 ISSN: 0305-1048
Copyright Statement
The Author(s) 2009. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.