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PMID: 21764772 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Resistance of bulky DNA lesions to nucleotide excision repair can result from extensive aromatic lesion-base stacking interactions.

Nucleic acids research ·Vol. 39 ·No. 20 ·2011-11-01 ·Pages 8752-64

Reeves DA, Mu H, Kropachev K, Cai Y, Ding S, Kolbanovskiy A, Kolbanovskiy M, Chen Y, Krzeminski J, Amin S, Patel DJ, Broyde S, Geacintov NE

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.

MeSH Terms
Base Pairing Benzopyrenes/chemistry DNA Adducts/chemistry DNA Damage DNA Repair Deoxyguanosine/analogs & derivatives,chemistry HeLa Cells Humans Imidazoles/chemistry Models, Molecular Nucleic Acid Conformation
Chemicals
2-amino-1-methyl-6-phenolimidazo(4,5-b)pyridine-DNA adduct Benzopyrenes DNA Adducts Imidazoles benzo(a)pyrene N2-dG adduct Deoxyguanosine
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Reeves Dara A
Department of Chemistry, Department of Biology, New York University, New York, NY 10003, USA.
Mu Hong
Kropachev Konstantin
Cai Yuqin
Ding Shuang
Kolbanovskiy Alexander
Kolbanovskiy Marina
Chen Ying
Krzeminski Jacek
Amin Shantu
Patel Dinshaw J
Broyde Suse
Geacintov Nicholas E
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Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
1362-4962
DOI
10.1093/nar/gkr537
Published
2011-11-01
Epub
2011-00-15
Pages
8752-64
Language
English
Region
England
NLM ID
0411011
PMCID
PMC3203604
Subset
IM
Grants
NCI NIH HHS · CA-28038 · United States
NCI NIH HHS · R01 CA028038 · United States
NCI NIH HHS · R01 CA075449 · United States
NCRR NIH HHS · C06 RR-16572 · United States
NCI NIH HHS · CA-099194 · United States
NCI NIH HHS · CA-046533 · United States
NCI NIH HHS · CA-75449 · United States
External Links
PubMed source DOI: 10.1093/nar/gkr537 PMC Full Text View journal details
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