Base pair conformation-dependent excision of Benzo[a]pyrene diol epoxide-guanine adducts by human nucleotide excision repair enzymes
Base pair conformation-dependent excision of Benzo[a]pyrene diol epoxide-guanine adducts by human nucleotide excision repair enzymes
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DOI：
10.1128/mcb.17.12.7069
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发表时间：
1997-12-01
影响因子：
5.3
通讯作者：
Naegeli, H
中科院分区：
文献类型：
--
作者：
Hess, MT;Gunz, D;Naegeli, H
人类核苷酸切除修复过程中致癌物-DNA加合物在高度可变的速度，甚至在相邻的网站沿着个别基因，在这里，我们确定的构象决定因素的快速或缓慢修复的N-2-鸟嘌呤加合物形成的苯并[a]芘二醇环氧化物（BPDE），一个强大的和普遍存在的诱变剂，主要诱导G.C-->T。A颠换和移码缺失。我们发现，人核苷酸切除修复处理主要的（+）-反式-BPDE-N-2-dG加合物的效率比相同序列中的标准乙酰氨基芴-C-8-dG损伤低15倍。在（+）-反式-和（-）-反式-BPDE-N-2-dG之间没有观察到差异，但通过将加合物构型改变为（+）-cis-或（-）-cis-BPDE-N-2-dG，切除增强约10倍。相反，当互补胞嘧啶被腺嘌呤取代时，（+）-顺式-和（-）-顺式-但不是（+）-反式-BPDE-N-2-dG的切除减少约10倍，并且当互补脱氧核糖核苷酸缺失时，这些BPDE损伤的切除基本上被消除。因此，一组化学上相同的BPDE加合物产生大于100倍范围的修复率，证明核苷酸切除修复活性完全由局部DNA构象决定，特别是，结构高度确定的底物之间的这种独特比较表明BPDE-N-2-dG损伤的快速切除与互补链中修饰的鸟嘌呤及其配偶体碱基从其正常螺旋内位置的置换相关，位于缺失位点对面的致癌物-DNA加合物的非常缓慢的切除揭示了一种细胞策略，该策略最大限度地减少了诱变translesion合成后的移码固定。
Human nucleotide excision repair processes carcinogen-DNA adducts at highly variable rates, even at adjacent sites along individual genes, Here, we identify conformational determinants of fast or slow repair by testing excision of N-2-guanine adducts formed by benzo[a]pyrene diol epoxide (BPDE), a potent and ubiquitous mutagen that induces mainly G.C-->T. A transversions and frameshift deletions. We found that human nucleotide excision repair processes the predominant (+)-trans-BPDE-N-2-dG adduct 15 times less efficiently than a standard acetylaminofluorene-C-8-dG lesion in the same sequence, No difference was observed between (+)-trans- and (-)-trans-BPDE-N-2-dG, but excision was enhanced about 10-fold by changing the adduct configurations to either (+)-cis- or (-)-cis-BPDE-N-2-dG. Conversely, excision of (+)-cis- and (-)-cis- but not (+)-trans-BPDE-N-2-dG was reduced about 10-fold when the complementary cytosine was replaced by adenine, and excision of these BPDE lesions was essentially abolished when the complementary deoxyribonucleotide was missing, Thus, a set of chemically identical BPDE adducts yielded a greater-than-100-fold range of repair rates, demonstrating that nucleotide excision repair activity is entirely dictated by local DNA conformation, In particular, this unique comparison between structurally highly defined substrates shows that fast excision of BPDE-N-2-dG lesions is correlated with displacement of both the modified guanine and its partner base in the complementary strand from their normal intrahelical positions, The very slow excision of carcinogen-DNA adducts located opposite deletion sites reveals a cellular strategy that minimizes the fixation of frameshifts after mutagenic translesion synthesis.