Journal
NUCLEIC ACIDS RESEARCH
Volume 38, Issue 2, Pages 428-440Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkp844
Keywords
-
Categories
Funding
- National Institutes of Health [R01 CA-055678, P30 ES-000267, R01 ES-013324]
- NATIONAL CANCER INSTITUTE [R01CA055678] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES009127, R01ES013324, P30ES000267] Funding Source: NIH RePORTER
Ask authors/readers for more resources
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 N-6 amine protons undergo increased solvent exchange. Stacking between Tg and the 3'-neighbor G center dot C base pair is disrupted. The solvent accessible surface and T-2 relaxation of Tg increases. Molecular dynamics calculations predict that the axial conformation of the Tg CH3 group is favored; propeller twisting of the Tg center dot 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 center dot C base pair. This may facilitate flipping both base pairs from the helix, enabling XPC/HR23B recognition prior to recruitment of XPA.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available