title: Resistance of bulky DNA lesions to nucleotide excision repair can result from extensive aromatic lesion-base stacking interactions.
abstract: The molecular basis of resistance to nucleotide excision repair (NER) of certain bulky DNA lesions is poorly understood. To address this issue, we have studied NER in human HeLa cell extracts of two topologically distinct lesions, one derived from benzo[a]pyrene (10R-(+)-cis-anti-B[a]P-N(2)-dG), and one from the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (C8-dG-PhIP), embedded in either full or 'deletion' duplexes (the partner nucleotide opposite the lesion is missing). All lesions adopt base-displaced intercalated conformations. Both full duplexes are thermodynamically destabilized and are excellent substrates of NER. However, the identical 10R-(+)-cis-anti-B[a]P-N(2)-dG adduct in the deletion duplex dramatically enhances the thermal stability of this duplex, and is completely resistant to NER. Molecular dynamics simulations show that B[a]P lesion-induced distortion/destabilization is compensated by stabilizing aromatic ring system-base stacking interactions. In the C8-dG-PhIP-deletion duplex, the smaller size of the aromatic ring system and the mobile phenyl ring are less stabilizing and yield moderate NER efficiency. Thus, a partner nucleotide opposite the lesion is not an absolute requirement for the successful initiation of NER. Our observations are consistent with the hypothesis that carcinogen-base stacking interactions, which contribute to the local DNA stability, can prevent the successful insertion of an XPC β-hairpin into the duplex and the normal recruitment of other downstream NER factors.
authors.affiliation: Department of Chemistry, Department of Biology, New York University, New York, NY 10003, USA.
authors.forename: Dara A
authors.initials: DA
authors.lastname: Reeves
authors.forename: Hong
authors.initials: H
authors.lastname: Mu
authors.forename: Konstantin
authors.initials: K
authors.lastname: Kropachev
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Cai
authors.forename: Shuang
authors.initials: S
authors.lastname: Ding
authors.forename: Alexander
authors.initials: A
authors.lastname: Kolbanovskiy
authors.forename: Marina
authors.initials: M
authors.lastname: Kolbanovskiy
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Jacek
authors.initials: J
authors.lastname: Krzeminski
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
authors.forename: Suse
authors.initials: S
authors.lastname: Broyde
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Geacintov
mesh_terms: D020029:Base Pairing; D001580:Benzopyrenes / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D004249:DNA Damage; D004260:DNA Repair; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation
chemical_list: C502239:2-amino-1-methyl-6-phenolimidazo(4,5-b)pyridine-DNA adduct; D001580:Benzopyrenes; D018736:DNA Adducts; D007093:Imidazoles; C478198:benzo(a)pyrene N2-dG adduct; D003849:Deoxyguanosine