Journal
NUCLEIC ACIDS RESEARCH
Volume 42, Issue 8, Pages 5020-5032Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gku162
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Funding
- National Institutes of Health (NIH) [R01 ES 011589, CA-168469, CA-75449]
- National Center for Research Resources, National Institutes of Health [C06 RR-16572]
- Ministero dell' Istruzione, dell' Universita' della Ricerca [PRIN-2009K3RH7N_002]
- Marie Curie Intra-European Fellowship [CYCLOGUO298555]
- NIH [R01 CA-75449]
- [R01 CA28038]
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The hydroxyl radical is a powerful oxidant that generates DNA lesions including the stereoisomeric R and S 5',8-cyclo-2'-deoxyadenosine (cdA) and 5',8-cyclo-2'-deoxyguanosine (cdG) pairs that have been detected in cellular DNA. Unlike some other oxidatively generated DNA lesions, cdG and cdA are repaired by the human nucleotide excision repair (NER) apparatus. The relative NER efficiencies of all four cyclopurines were measured and compared in identical human HeLa cell extracts for the first time under identical conditions, using identical sequence contexts. The cdA and cdG lesions were excised with similar efficiencies, but the efficiencies for both 5'R cyclopurines were greater by a factor of similar to 2 than for the 5'S lesions. Molecular modeling and dynamics simulations have revealed structural and energetic origins of this difference in NER-incision efficiencies. These lesions cause greater DNA backbone distortions and dynamics relative to unmodified DNA in 5'R than in 5'S stereoisomers, producing greater impairment in van der Waals stacking interaction energies in the 5'R cases. The locally impaired stacking interaction energies correlate with relative NER incision efficiencies, and explain these results on a structural basis in terms of differences in dynamic perturbations of the DNA backbone imposed by the R and S covalent 5',8 bonds.
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