The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer
The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer
复制标题
DOI：
10.1074/jbc.274.10.6336
复制
发表时间：
1999-03-05
影响因子：
4.8
通讯作者：
Fishel, R
中科院分区：
文献类型：
--
作者：
Guerrette, S;Acharya, S;Fishel, R
两种人类错配修复（MMR）基因hMSH2和hMLH1的种系突变似乎占常见癌症易感性综合征遗传性非息肉病性结直肠癌（HNPCC）的约70%。虽然hMLH1蛋白已被发现与另一种MMR蛋白hPMS2作为异源二聚体进行聚合，但它们在MMR中的功能尚不清楚。在这项研究中，我们已经确定了hMLH1与hPMS2的物理相互作用区域。然后，我们检查了在HNPCC种类中发现的hMLH1错义改变对其与hPMS2相互作用的影响。其中4个错义改变（L574P、K616 Delta、R659P和A681T）与hPMS2的结合减少了约95%。另外两个错义改变（K618A和K618T）与hPMS2的结合降低了约85%，而三个错义改变（S44F， V506A和E578G）与hPMS2的结合降低了25-65%。有趣的是，包含在共识相互作用区域内的两个HNPCC错意改变（Q542L和L582V）对与hPMS2的相互作用没有影响，这表明它们可能影响hMLH1的其他功能。这些数据证实，hMLH1与hPMS2相互作用中的功能缺陷与HNPCC相关，并表明人类MutL同源物的其他未知功能改变可能导致HNPCC种类的肿瘤发生。
Germline mutations in two human mismatch repair (MMR) genes, hMSH2 and hMLH1, appear to account for approximately 70% of the common cancer susceptibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC). Although the hMLH1 protein has been found to copurify with another MMR protein hPMS2 as a heterodimer, their function in MMR is unknown. In this study, we have identified the physical interaction regions of both hMLH1 with hPMS2. We then examined the effects of hMLH1 missense alterations found in HNPCC kindreds for their interaction with hPMS2. Four of these missense alterations (L574P, K616 Delta, R659P, and A681T) displayed >95% reduction in binding to hPMS2. Two additional missense alterations (K618A and K618T) displayed a >85% reduction in binding to hPMS2, whereas three missense alterations (S44F, V506A, and E578G) displayed 25-65% reduction in binding to hPMS2. Interestingly, two HNPCC missense alterations (Q542L and L582V) contained within the consensus interaction region displayed no effect on interaction with hPMS2, suggesting that they may affect other functions of hMLH1. These data confirm that functional deficiencies in the interaction of hMLH1 with hPMS2 are associated with HNPCC as well as suggest that other unknown functional alteration of the human MutL homologues may lead to tumorigenesis in HNPCC kindreds.