Binding of insertion/deletion DNA mismatches by the heterodimer of yeast mismatch repair proteins MSH2 and MSH3
Binding of insertion/deletion DNA mismatches by the heterodimer of yeast mismatch repair proteins MSH2 and MSH3
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DOI：
10.1016/s0960-9822(02)70686-6
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发表时间：
1996-09-01
期刊：
影响因子：
9.2
通讯作者：
Prakash, S
中科院分区：
文献类型：
--
作者：
Habraken, Y;Sung, P;Prakash, S
DNA错配修复从新复制的DNA链中去除错配。在人类中，错配修复基因hMSH 2、hMLH 1、hPMS 1和hPMS 2的突变导致遗传性非息肉病性结直肠癌（HNPCC）[1-8]。hMSH 2（MutS同源物的MSH）蛋白与160 kDa蛋白形成复合物，该异源二聚体hMutS α对G/T错配具有高亲和力[9，10]。其中hMutS α的160 kDa亚基突变的细胞系在碱基-碱基和单核苷酸插入/缺失错配的修复中特异性缺陷[9，11]。遗传学研究表明，S.酿酒酵母的研究表明，MSH 2与MSH 3或MSH 6在错配修复中起作用，并且在后两种基因不存在时，MSH 2是无活性的[12，13]。MSH 6编码hMutS α的160 kDa亚基的酵母对应物[12，13]。与人类一样，酵母MSH 6与MSH 2形成复合物，MSH 2-MSH 6异二聚体结合G/T错配[14]。在这里，我们发现，MSH 2和MSH 3形成另一个稳定的异源二聚体，我们纯化这个异源二聚体接近同质。我们发现，MSH 2-MSH 3对G/T错配的亲和力低，但与MSH 2-MSH 6不同，其以高特异性结合插入/缺失错配。
DNA-mismatch repair removes mismatches from the newly replicated DNA strand. In humans, mutations in the mismatch repair genes hMSH2, hMLH1, hPMS1 and hPMS2 result in hereditary non-polyposis colorectal cancer (HNPCC) [1-8]. The hMSH2 (MSH for MutS homologue) protein forms a complex with a 160 kDa protein, and this heterodimer, hMutS alpha, has high affinity for a G/T mismatch [9,10]. Cell lines in which the 160 kDa subunit of hMutS alpha is mutated are specifically defective in the repair of base-base and single-nucleotide insertion/deletion mismatches [9,11]. Genetic studies in S. cerevisiae have suggested that MSH2 functions with either MSH3 or MSH6 in mismatch repair, and, in the absence of the latter two genes, MSH2 is inactive [12,13]. MSH6 encodes the yeast counterpart of the 160 kDa subunit of hMutS alpha [12,13]. As in humans, yeast MSH6 forms a complex with MSH2, and the MSH2-MSH6 heterodimer binds a G/T mismatch [14]. Here, we find that MSH2 and MSH3 form another stable heterodimer, and we purify this heterodimer to near homogeneity. We show that MSH2-MSH3 has low affinity for a G/T mismatch but binds to insertion/deletion mismatches with high specificity, unlike MSH2-MSH6.