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

Dara A. Reeves, Hong Mu, Konstantin Kropachev, Yuqin Cai, Shuang Ding, Alexander Kolbanovskiy, Marina Kolbanovskiy, Ying Chen, Jacek Krzeminski, Shantu Amin, Dinshaw J. Patel, Suse Broyde, Nicholas E. Geacintov

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)8752-8764
Number of pages13
JournalNucleic acids research
Volume39
Issue number20
DOIs
StatePublished - Nov 1 2011

ASJC Scopus subject areas

  • Genetics

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    Reeves, D. A., Mu, H., Kropachev, K., Cai, Y., Ding, S., Kolbanovskiy, A., Kolbanovskiy, M., Chen, Y., Krzeminski, J., Amin, S., Patel, D. J., Broyde, S., & Geacintov, N. E. (2011). Resistance of bulky DNA lesions to nucleotide excision repair can result from extensive aromatic lesion-base stacking interactions. Nucleic acids research, 39(20), 8752-8764. https://doi.org/10.1093/nar/gkr537