hMRE11 deficiency leads to microsatellite instability and defective DNA mismatch repair
hMRE11 deficiency leads to microsatellite instability and defective DNA mismatch repair
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DOI：
10.1038/sj.embor.7400392
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发表时间：
2005-05
期刊：
影响因子：
7.7
通讯作者：
A. Vo;Fengxue Zhu;Xiling Wu;F. Yuan;Yin Gao;L. Gu;Guo-Min Li;Tai-Hsien Lee;C. Her
中科院分区：
文献类型：
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作者：
A. Vo;Fengxue Zhu;Xiling Wu;F. Yuan;Yin Gao;L. Gu;Guo-Min Li;Tai-Hsien Lee;C. Her
DNA错配修复（MMR）在监测遗传信息的准确传递中是必不可少的，该途径的缺陷导致微卫星不稳定性和遗传性非息肉病性结直肠癌（HNPCC）。我们先前的研究提出了hMRE 11可能通过与hMLH 1的物理相互作用参与MMR的可能性。在这里，我们表明hMRE 11缺陷导致单核苷酸和二核苷酸序列的MSI显著增加。此外，HeLa细胞中RNA干扰介导的hMRE 11敲低导致MMR缺陷。对位于hMRE 11相互作用结构域内的7个HNPCC相关hMLH 1错义突变的分析表明，4个突变（L574 P、K618 T、R659 P和A681 T）导致hMRE 11和hMLH 1之间的相互作用几乎完全中断，2个突变（Q542 L和L582 V）导致蛋白质相互作用减少30%。这些发现表明，hMRE 11代表了MMR通路的功能组分，hMLH 1-hMRE 11相互作用的破坏可能是HNPCC肿瘤亚组中hMLH 1突变的另一种分子解释。
DNA mismatch repair (MMR) is essential in the surveillance of accurate transmission of genetic information, and defects in this pathway lead to microsatellite instability and hereditary nonpolyposis colorectal cancer (HNPCC). Our previous study raised the possibility that hMRE11 might be involved in MMR through physical interaction with hMLH1. Here, we show that hMRE11 deficiency leads to significant increase in MSI for both mono‐ and dinucleotide sequences. Furthermore, RNA‐interference‐mediated hMRE11‐knockdown in HeLa cells results in MMR deficiency. Analysis of seven HNPCC‐associated hMLH1 missense mutations located within the hMRE11‐interacting domain shows that four mutations (L574P, K618T, R659P and A681T) cause near‐complete disruption of the interaction between hMRE11 and hMLH1, and two mutations (Q542L and L582V) cause a 30% reduction of protein interaction. These findings indicate that hMRE11 represents a functional component of the MMR pathway and the disruption of hMLH1–hMRE11 interaction could be an alternative molecular explanation for hMLH1 mutations in a subset of HNPCC tumours.