title: Structural basis for the recognition of diastereomeric 5',8-cyclo-2'-deoxypurine lesions by the human nucleotide excision repair system.
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.
authors.affiliation: Department of Chemistry New York University, 100 Washington Square East, New York, NY 10003, USA, Department of Biology, New York University, 100 Washington Square East, New York, NY 10003, USA and Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, 40129 Bologna, Italy.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Kropachev
authors.forename: Shuang
authors.initials: S
authors.lastname: Ding
authors.forename: Michael A
authors.initials: MA
authors.lastname: Terzidis
authors.forename: Annalisa
authors.initials: A
authors.lastname: Masi
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Cai
authors.forename: Marina
authors.initials: M
authors.lastname: Kolbanovskiy
authors.forename: Chryssostomos
authors.initials: C
authors.lastname: Chatgilialoglu
authors.forename: Suse
authors.initials: S
authors.lastname: Broyde
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Geacintov
authors.forename: Vladimir
authors.initials: V
authors.lastname: Shafirovich
mesh_terms: D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair; D003839:Deoxyadenosines / Q000737:chemistry*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D013237:Stereoisomerism
chemical_list: D003839:Deoxyadenosines; C050888:8,5'-cyclo-2'-deoxyguanosine; C056752:8,5'-cyclo-2'-deoxyadenosine; D004247:DNA; D003849:Deoxyguanosine