Structural basis for removal of adenine mispaired with 8-oxoguanine by MutY adenine DNA glycosylase
Structural basis for removal of adenine mispaired with 8-oxoguanine by MutY adenine DNA glycosylase
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DOI：
10.1038/nature02306
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发表时间：
2004-02-12
期刊：
影响因子：
64.8
通讯作者：
Verdine, GL
中科院分区：
文献类型：
--
作者：
Fromme, JC;Banerjee, A;Verdine, GL
需氧生物的基因组遭受鸟嘌呤的慢性氧化，产生基因毒性产物8-氧鸟嘌呤（oxoG）(1)。复制性DNA聚合酶误读氧化基残基并插入腺嘌呤而不是胞嘧啶。由此产生的a.o og错配中的两个碱基都是诱变损伤，必须进行碱基特异性替换以恢复原始的C.G对。这样做对DNA修复机制来说是一个巨大的挑战，因为在大多数基因组中，腺嘌呤大约占碱基的25%。进化上保守的腺嘌呤DNA糖基酶（在细菌中称为MutY，在人类中称为hMYH）通过从DNA主干中去除不合适配对的腺嘌呤碱基，启动A.oxoG到C.G的修复。关于MutY功能的一个中心问题是a.o oxog错配在大量A.T对中被靶向的机制。在这里，我们报告使用二硫化物交联(2)获得MutY-DNA损伤识别复合物的高分辨率晶体结构。这些结构揭示了识别a.o oxog对中的病变和催化腺嘌呤碱基去除的基础。
The genomes of aerobic organisms suffer chronic oxidation of guanine to the genotoxic product 8-oxoguanine (oxoG)(1). Replicative DNA polymerases misread oxoG residues and insert adenine instead of cytosine opposite the oxidized base. Both bases in the resulting A.oxoG mispair are mutagenic lesions, and both must undergo base-specific replacement to restore the original C.G pair. Doing so represents a formidable challenge to the DNA repair machinery, because adenine makes up roughly 25% of the bases in most genomes. The evolutionarily conserved enzyme adenine DNA glycosylase (called MutY in bacteria and hMYH in humans) initiates repair of A.oxoG to C.G by removing the inappropriately paired adenine base from the DNA backbone. A central issue concerning MutY function is the mechanism by which A.oxoG mispairs are targeted among the vast excess of A.T pairs. Here we report the use of disulphide crosslinking(2) to obtain high-resolution crystal structures of MutY-DNA lesion-recognition complexes. These structures reveal the basis for recognizing both lesions in the A.oxoG pair and for catalysing removal of the adenine base.