Habraken Y, Sung P, Prakash L, Prakash S
Sealy Center for Molecular Science, University of Texas Medical Branch, 6.104 Medical Research Building, 11th & Mechanic Streets, Galveston, Texas 77555-1061, USA.
Curr Biol. 1996 Sep 1;6(9):1185-7. doi: 10.1016/s0960-9822(02)70686-6.
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, hMutSalpha, has high affinity for a G/T mismatch [9,10]. Cell lines in which the 160 kDa subunit of hMutSalpha 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 hMutSalpha [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.
DNA错配修复可从新复制的DNA链中去除错配。在人类中，错配修复基因hMSH2、hMLH1、hPMS1和hPMS2发生突变会导致遗传性非息肉病性结直肠癌（HNPCC）[1-8]。hMSH2（MutS同源物MSH）蛋白与一种160 kDa的蛋白形成复合物，这种异二聚体hMutSalpha对G/T错配具有高亲和力[9,10]。hMutSalpha的160 kDa亚基发生突变的细胞系在碱基-碱基错配和单核苷酸插入/缺失错配的修复中存在特异性缺陷[9,11]。酿酒酵母中的遗传学研究表明，MSH2在错配修复中与MSH3或MSH6协同发挥作用，并且在缺少后两个基因的情况下，MSH2无活性[12,13]。MSH6编码hMutSalpha的160 kDa亚基的酵母对应物[12,13]。与人类一样，酵母MSH6与MSH2形成复合物，并且MSH2-MSH6异二聚体结合G/T错配[
