Distant Neighbor Base Sequence Context Effects in Human Nucleotide Excision Repair of a Benzo[a]pyrene-derived DNA Lesion |
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Authors: | Yuqin Cai Rong Xu Yijin Tang Alexander Kolbanovskii Dinshaw J Patel Nicholas E Geacintov |
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Institution: | 1 Department of Biology, New York University, New York, NY 10003, USA 2 Department of Chemistry, New York University, New York, NY 10003, USA 3 Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA 4 Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA |
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Abstract: | The effects of non-nearest base sequences, beyond the nucleotides flanking a DNA lesion on either side, on nucleotide excision repair (NER) in extracts from human cells were investigated. We constructed two duplexes containing the same minor groove-aligned 10S (+)-trans-anti-Ba]P-N2-dG (G?) DNA adduct, derived from the environmental carcinogen benzoa]pyrene (Ba]P): 5′-C-C-A-T-C-G?-C-T-A-C-C-3′ (CG?C-I), and 5′-C-A-C3-A4-C5-G?-C-A-C-A-C-3′ (CG?C-II). We used polyacrylamide gel electrophoresis to compare the extent of DNA bending, and molecular dynamics simulations to analyze the structural characteristics of these two DNA duplexes. The NER efficiencies are 1.6(± 0.2)-fold greater in the case of the CG?C-II than the CG?C-I sequence context in 135-mer duplexes. Gel electrophoresis and self-ligation circularization experiments revealed that the CG?C-II duplex is more bent than the CG?C-I duplex, while molecular dynamics simulations showed that the unique -C3-A4-C5- segment in the CG?C-II duplex plays a key role. The presence of a minor groove-positioned guanine amino group, the Watson-Crick partner to C3, acts as a wedge; facilitated by a highly deformable local -C3-A4- base step, this amino group allows the Ba]P ring system to produce a more enlarged minor groove in CG?C-II than in CG?C-I, as well as a local untwisting and enlarged and flexible Roll only in the CG?C-II sequence. These structural properties fit well with our earlier findings that in the case of the family of minor groove 10S (+)-trans-anti-Ba]P-N2-dG lesions, flexible bends and enlarged minor groove widths constitute NER recognition signals, and extend our understanding of sequence context effects on NER to the neighbors that are distant to the lesion. |
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Keywords: | NER nucleotide excision repair B[a]P benzo[a]pyrene B[a]PDE benzo[a]pyrene diol epoxide (+)-anti-B[a]PDE (+)-(7R 8S 9S 10R)-7 8-dihydroxy-9 10-epoxy-7 8 9 10-tetrahydrobenzo[a]pyrene MD molecular dynamics SASA solvent-accessible surface area |
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