Nucleotide excision repair of 2-acetylaminofluorene-and 2-aminofluorene-(C8)-guanine adducts

Molecular dynamics simulations elucidate how lesion structure and base sequence context impact repair efficiencies

Hong Mu, Konstantin Kropachev, Lihua Wang, Lu Zhang, Alexander Kolbanovskiy, Marina Kolbanovskiy, Nicholas E. Geacintov, Suse Broyde

Research output: Contribution to journalArticle

Abstract

Nucleotide excision repair (NER) efficiencies of DNA lesions can vary by orders of magnitude, for reasons that remain unclear. An example is the pair of N-(2′-deoxyguanosin-8-yl)-2-aminofluorene (dG-C8-AF) and N-(20-deoxyguanosin-8-yl)-2-acetylaminofluorene (dG-C8-AAF) adducts that differ by a single acetyl group. The NER efficiencies in human HeLa cell extracts of these lesions are significantly different when placed at G1, G 2 or G3 in the duplex sequence (5′-CTCG1G2CG3CCATC- 3′) containing the NarI mutational hot spot. Furthermore, the dG-C8-AAF adduct is a better substrate of NER than dG-C8-AF in all three NarI sequence contexts. The conformations of each of these adducts were investigated by Molecular dynamics (MD) simulation methods. In the base-displaced conformational family, the greater repair susceptibility of dG-C8-AAF in all sequences stems from steric hindrance effects of the acetyl group which significantly diminish the adduct-base stabilizing van der Waals stacking interactions relative to the dG-C8-AF case. Base sequence context effects for each adduct are caused by differences in helix untwisting and minor groove opening that are derived from the differences in stacking patterns. Overall, the greater NER efficiencies are correlated with greater extents of base sequence-dependent local untwisting and minor groove opening together with weaker stacking interactions.

Original languageEnglish (US)
Pages (from-to)9675-9690
Number of pages16
JournalNucleic Acids Research
Volume40
Issue number19
DOIs
StatePublished - Oct 2012

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2-Acetylaminofluorene
Guanine
Molecular Dynamics Simulation
DNA Repair
Cell Extracts
HeLa Cells
2-aminofluorene
DNA

ASJC Scopus subject areas

  • Genetics

Cite this

Nucleotide excision repair of 2-acetylaminofluorene-and 2-aminofluorene-(C8)-guanine adducts : Molecular dynamics simulations elucidate how lesion structure and base sequence context impact repair efficiencies. / Mu, Hong; Kropachev, Konstantin; Wang, Lihua; Zhang, Lu; Kolbanovskiy, Alexander; Kolbanovskiy, Marina; Geacintov, Nicholas E.; Broyde, Suse.

In: Nucleic Acids Research, Vol. 40, No. 19, 10.2012, p. 9675-9690.

Research output: Contribution to journalArticle

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abstract = "Nucleotide excision repair (NER) efficiencies of DNA lesions can vary by orders of magnitude, for reasons that remain unclear. An example is the pair of N-(2′-deoxyguanosin-8-yl)-2-aminofluorene (dG-C8-AF) and N-(20-deoxyguanosin-8-yl)-2-acetylaminofluorene (dG-C8-AAF) adducts that differ by a single acetyl group. The NER efficiencies in human HeLa cell extracts of these lesions are significantly different when placed at G1, G 2 or G3 in the duplex sequence (5′-CTCG1G2CG3CCATC- 3′) containing the NarI mutational hot spot. Furthermore, the dG-C8-AAF adduct is a better substrate of NER than dG-C8-AF in all three NarI sequence contexts. The conformations of each of these adducts were investigated by Molecular dynamics (MD) simulation methods. In the base-displaced conformational family, the greater repair susceptibility of dG-C8-AAF in all sequences stems from steric hindrance effects of the acetyl group which significantly diminish the adduct-base stabilizing van der Waals stacking interactions relative to the dG-C8-AF case. Base sequence context effects for each adduct are caused by differences in helix untwisting and minor groove opening that are derived from the differences in stacking patterns. Overall, the greater NER efficiencies are correlated with greater extents of base sequence-dependent local untwisting and minor groove opening together with weaker stacking interactions.",
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