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首页> 外文期刊>Mutation Research: International Journal on Mutagenesis, Chromosome Breakage and Related Subjects >Functional analysis of HNPCC-related missense mutations in MSH2.
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Functional analysis of HNPCC-related missense mutations in MSH2.

机译：MSH2中HNPCC相关的错义突变的功能分析。

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Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germline mutations in the human DNA mismatch repair (MMR) genes, most frequently MSH2 and MLH1. The majority of HNPCC mutations cause truncations and thus loss of function of the affected polypeptide. However, a significant proportion of MMR mutations found in HNPCC patients are single amino acid substitutions and the functional consequences of many of these mutations in DNA repair are unclear. We have examined the consequences of seven MSH2 missense mutations found in HNPCC families by testing the MSH2 mutant proteins in functional assays as well as by generating equivalent missense mutations in Escherichia coli MutS and analyzing the phenotypes of these mutants. Here we show that two mutant proteins, MSH2-P622L and MSH2-C697F confer multiple biochemical defects, namely in mismatch binding, in vivo interaction with MSH6 and EXO1, and in nuclear localization in the cell. Mutation G674R, located in the ATP-binding region of MSH2, appears to confer resistance to ATP-dependent mismatch release. Mutations D167H and H639R show reduced mismatch binding. Results of in vivo experiments in E. coli with MutS mutants show that one additional mutant, equivalent of MSH2-A834T that do not show any defects in MSH2 assays, is repair deficient. In conclusion, all mutant proteins (except for MSH2-A305T) have defects; either in mismatch binding, ATP-release, mismatch repair activity, subcellular localization or protein-protein interactions.
机译：遗传性非息肉性结直肠癌（HNPCC）与人类DNA错配修复（MMR）基因中的种系突变相关，最常见的是MSH2和MLH1。大多数HNPCC突变会导致截短，从而影响多肽的功能丧失。但是，在HNPCC患者中发现的大部分MMR突变是单个氨基酸取代，而且尚不清楚这些突变中许多突变在DNA修复中的功能后果。我们通过在功能测定中测试MSH2突变蛋白，以及通过在大肠杆菌MutS中产生等效的错义突变并分析这些突变体的表型，检查了在HNPCC家族中发现的7个MSH2错义突变的后果。在这里，我们显示了两个突变蛋白，MSH2-P622L和MSH2-C697F赋予了多个生化缺陷，即错配结合，与MSH6和EXO1的体内相互作用以及细胞中的核定位。位于MSH2的ATP结合区域的突变G674R似乎赋予了对ATP依赖性错配释放的抵抗力。突变D167H和H639R显示出减少的错配结合。在大肠杆菌中使用MutS突变体进行的体内实验结果表明，另外一种与MSH2-A834T等效且在MSH2分析中未显示任何缺陷的突变体修复不足。总之，所有突变蛋白（MSH2-A305T除外）均存在缺陷。错配结合，ATP释放，错配修复活性，亚细胞定位或蛋白质-蛋白质相互作用。

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