Understanding the role of the Q338H MUTYH variant in oxidative damage repair.
Understanding the role of the Q338H MUTYH variant in oxidative damage repair.
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DOI：
10.1093/nar/gkt130
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发表时间：
2013-04
影响因子：
14.9
通讯作者：
Mazzei F
中科院分区：
文献类型：
--
作者：
Turco E;Ventura I;Minoprio A;Russo MT;Torreri P;Degan P;Molatore S;Ranzani GN;Bignami M;Mazzei F
MUTYH DNA-糖基化酶通过去除错误掺入的氧化嘌呤对面的腺嘌呤，间接参与错误编码的7，8-二氢-8-氧代-2 ′-脱氧鸟嘌呤（8-oxodG）损伤的修复。MUTYH基因中的遗传双等位基因突变导致隐性综合征，MUTYH相关息肉病（MAP），其赋予结直肠癌的风险增加。在这项研究中，我们使用重组蛋白以及基于细胞的测定功能性地表征了Q338 H变体。这是人类结直肠癌基因中的常见变异，通常认为其与MAP表型无关，但最近表明其为低等位基因。我们证明Q338 H变体在体外保留了野生型DNA糖基化酶活性，但与复制传感器RAD 9：RAD 1：HUS 1（9-1-1）复合物相互作用的能力降低。与表达野生型MUTYH cDNA的Mutyh−/−小鼠胚胎成纤维细胞相比，Q338 H变体的表达与DNA 8-oxodG水平的增加、对氧化剂的超敏反应和细胞周期S期的群体积累有关。因此，MUTYH与9-1-1复合物的无效相互作用导致修复缺陷型表型，表明MUTYH酶功能和S期检查点之间的适当通信是氧化损伤的有效修复所需的。
The MUTYH DNA–glycosylase is indirectly engaged in the repair of the miscoding 7,8-dihydro-8-oxo-2′-deoxyguanine (8-oxodG) lesion by removing adenine erroneously incorporated opposite the oxidized purine. Inherited biallelic mutations in the MUTYH gene are responsible for a recessive syndrome, the MUTYH-associated polyposis (MAP), which confers an increased risk of colorectal cancer. In this study, we functionally characterized the Q338H variant using recombinant proteins, as well as cell-based assays. This is a common variant among human colorectal cancer genes, which is generally considered, unrelated to the MAP phenotype but recently indicated as a low-penetrance allele. We demonstrate that the Q338H variant retains a wild-type DNA–glycosylase activity in vitro, but it shows a reduced ability to interact with the replication sensor RAD9:RAD1:HUS1 (9–1–1) complex. In comparison with Mutyh−/− mouse embryo fibroblasts expressing a wild-type MUTYH cDNA, the expression of Q338H variant was associated with increased levels of DNA 8-oxodG, hypersensitivity to oxidant and accumulation of the population in the S phase of the cell cycle. Thus, an inefficient interaction of MUTYH with the 9–1–1 complex leads to a repair-defective phenotype, indicating that a proper communication between MUTYH enzymatic function and the S phase checkpoint is needed for effective repair of oxidative damage.
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