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
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
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DOI：
10.1093/nar/gks788
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发表时间：
2012-10-01
影响因子：
14.9
通讯作者：
Broyde, Suse
中科院分区：
文献类型：
--
作者：
Mu, Hong;Kropachev, Konstantin;Broyde, Suse
DNA损伤的核苷酸切除修复（NER）效率可能会有数量级的变化，原因尚不清楚。一个例子是一对N-（2'-脱氧鸟苷-8-基）-2-氨基芴（dG-C8-AF）和N-（2'-脱氧鸟苷-8-基）-2-乙酰氨基芴（dG-C8-AAF）加合物，它们只相差一个乙酰基。当放置在含有NarI突变热点的双序列(5'-CTCG(1)G（2)CG(3)CCATC-3'）中的G(1)、G(2)或G(3)位置时，这些病变的人HeLa细胞提取物的NER效率有显著差异。此外，在所有三种NarI序列背景下，dG-C8-AAF加合物比dG-C8-AF是更好的NER底物。用分子动力学（MD）模拟方法研究了这些加合物的构象。在碱基置换构象家族中，dG-C8-AAF在所有序列中都具有更大的修复易感性，这是由于乙酰基的空间位阻效应，相对于dG-C8-AF，乙酰基的空间位阻效应显著降低了加合物-碱基稳定范德华叠加相互作用。每个加合物的碱基序列环境效应是由不同的螺旋解扭和微小的槽开度引起的，这是由不同的堆叠模式引起的。总体而言，更高的NER效率与碱基序列依赖的更大程度的局部解扭和较小的槽开度以及较弱的堆叠相互作用相关。
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-(2'-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 G(1), G(2) or G(3) in the duplex sequence (5'-CTCG(1)G(2)CG(3)CCATC-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.