TY - JOUR
T1 - Structural basis for the recognition of diastereomeric 5′,8-cyclo- 2′-deoxypurine lesions by the human nucleotide excision repair system
AU - Kropachev, Konstantin
AU - Ding, Shuang
AU - Terzidis, Michael A.
AU - Masi, Annalisa
AU - Liu, Zhi
AU - Cai, Yuqin
AU - Kolbanovskiy, Marina
AU - Chatgilialoglu, Chryssostomos
AU - Broyde, Suse
AU - Geacintov, Nicholas E.
AU - Shafirovich, Vladimir
N1 - Funding Information:
This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation (NSF) grant MCB060037, as well as the computational resources provided by NYU-ITS. Author Contributions: K.K. and M.K. carried out the NER experiments. M.A.T. A.M and C.C. synthesized the lesion-containing oligonucleotides, and Z.L. carried out the thermal melting studies. The computer modeling and molecular dynamics simulations were carried out by S.D. with the help of Y.C. S.B. supervised the modeling and molecular dynamics studies, while V.S. and N.E.G. supervised the experimental repair and melting studies. V.S., N.E.G., S.B., S.D. and Y.C. analyzed the results. V.S., N.E.G., S.B. and S.D. wrote the manuscript. C.C. and N.E.G. conceived of the project.
Funding Information:
National Institutes of Health (NIH) [grant R01 ES 011589 to V.S., CA-168469 to N.E.G., and CA-75449 to S.B.]; Computational infrastructure and systems management were partially supported by [R01 CA28038 to S.B.]; Components of this work were conducted in the Shared Instrumentation Facility at NYU that was constructed with support from a Research Facilities Improvement [Grant C06 RR-16572] from the National Center for Research Resources, National Institutes of Health; Financial support from the Ministero dell’ Istruzione, dell’ Universita’ della Ricerca [PRIN-2009K3RH7N_002] and Marie Curie Intra-European Fellowship [CYCLOGUO298555] is gratefully acknowledged. Funding for open access charge: NIH [R01 CA-75449 to S.B.]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
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U2 - 10.1093/nar/gku162
DO - 10.1093/nar/gku162
M3 - Article
C2 - 24615810
AN - SCOPUS:84899802515
SN - 0305-1048
VL - 42
SP - 5020
EP - 5032
JO - Nucleic acids research
JF - Nucleic acids research
IS - 8
ER -