Structural basis for the recognition of diastereomeric 5′,8-cyclo- 2′-deoxypurine lesions by the human nucleotide excision repair system

Konstantin Kropachev, Shuang Ding, Michael A. Terzidis, Annalisa Masi, Zhi Liu, Yuqin Cai, Marina Kolbanovskiy, Chryssostomos Chatgilialoglu, Suse Broyde, Nicholas E. Geacintov, Vladimir Shafirovich

Research output: Contribution to journalArticlepeer-review

Abstract

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 ∼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.

Original languageEnglish (US)
Pages (from-to)5020-5032
Number of pages13
JournalNucleic acids research
Volume42
Issue number8
DOIs
StatePublished - Apr 2014

ASJC Scopus subject areas

  • Genetics

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