TY - JOUR
T1 - Nucleotide excision repair of 2-acetylaminofluorene-and 2-aminofluorene-(C8)-guanine adducts
T2 - Molecular dynamics simulations elucidate how lesion structure and base sequence context impact repair efficiencies
AU - Mu, Hong
AU - Kropachev, Konstantin
AU - Wang, Lihua
AU - Zhang, Lu
AU - Kolbanovskiy, Alexander
AU - Kolbanovskiy, Marina
AU - Geacintov, Nicholas E.
AU - Broyde, Suse
N1 - Funding Information:
In this work we used the computational resources of the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (NSF) and the multi-purpose high performance computing resource of New York University (NYU-ITS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
Funding Information:
National Institutes of Health (NIH) [CA-099194 to N.E.G., CA-75449 to S.B.]; Computational infrastructure and systems management [R01CA28038 to S.B., in part]; Components of this work were conducted in the Shared Instrumentation Facility at NYU that was constructed with support from a Research Facilities Improvement Grant [C06 RR-16572]; National Center for Research Resources, NIH; The acquisition of the MALDI-TOF mass spectrometer used in this work was supported by the National Science Foundation [CHE-0958457]. Funding for open access charge: NIH [CA-75449 to S.B.].
PY - 2012/10
Y1 - 2012/10
N2 - 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.
AB - 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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U2 - 10.1093/nar/gks788
DO - 10.1093/nar/gks788
M3 - Article
C2 - 22904073
AN - SCOPUS:84868133144
SN - 0305-1048
VL - 40
SP - 9675
EP - 9690
JO - Nucleic acids research
JF - Nucleic acids research
IS - 19
ER -