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

被引：66

作者：

Kropachev, Konstantin ^{[1
]}

Ding, Shuang ^{[2
]}

Terzidis, Michael A. ^{[3
]}

Masi, Annalisa ^{[3
]}

Liu, Zhi ^{[1
]}

Cai, Yuqin ^{[2
]}

Kolbanovskiy, Marina ^{[1
]}

Chatgilialoglu, Chryssostomos ^{[3
]}

Broyde, Suse ^{[2
]}

Geacintov, Nicholas E. ^{[1
]}

Shafirovich, Vladimir ^{[1
]}

机构：

[1] NYU, Dept Chem, New York, NY 10003 USA

[2] NYU, Dept Biol, New York, NY 10003 USA

[3] CNR, Ist Sintesi Organ & Fotoreattivita, I-40129 Bologna, Italy

来源：

NUCLEIC ACIDS RESEARCH | 2014年 / 42卷 / 08期

基金：

美国国家卫生研究院;

关键词：

RADICAL-INDUCED FORMATION; OXIDATIVE DNA-DAMAGE; HUMAN-CELLS; MOLECULAR-DYNAMICS; GUANINE ADDUCTS; NUCLEIC-ACIDS; FURANOSE RING; FORCE-FIELD; EFFICIENCIES; (5'S)-8,5'-CYCLO-2'-DEOXYGUANOSINE;

D O I：

10.1093/nar/gku162

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：5020 / 5032

页数：13

共 86 条

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