Habraken Y, Sung P, Prakash L, Prakash S
Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston 77555-1061, USA.
Curr Biol. 1997 Oct 1;7(10):790-3. doi: 10.1016/s0960-9822(06)00337-x.
DNA mismatch repair has a key role in maintaining genomic stability. Defects in mismatch repair cause elevated spontaneous mutation rates and increased instability of simple repetitive sequences, while mutations in human mismatch repair genes result in hereditary nonpolyposis colorectal cancers. Mismatch recognition represents the first critical step of mismatch repair. Genetic and biochemical studies in yeast and humans have indicated a requirement for MSH2-MSH3 and MSH2-MSH6 heterodimers in mismatch recognition. These complexes have, to some extent, overlapping mismatch binding specificities. MLH1 and PMS1 are the other essential components of mismatch repair, but how they function in this process is not known. We have purified the yeast MLH1-PMS1 heterodimer to near homogeneity, and examined its effect on MSH2-MSH3 binding to DNA mismatches. By itself, the MLH1-PMS1 complex shows no affinity for mismatched DNA, but it greatly enhances the mismatch binding ability of MSH2-MSH3.
DNA错配修复在维持基因组稳定性方面起着关键作用。错配修复缺陷会导致自发突变率升高以及简单重复序列的不稳定性增加，而人类错配修复基因的突变会导致遗传性非息肉病性结直肠癌。错配识别是错配修复的第一步关键步骤。在酵母和人类中的遗传及生化研究表明，错配识别需要MSH2-MSH3和MSH2-MSH6异二聚体。这些复合物在某种程度上具有重叠的错配结合特异性。MLH1和PMS1是错配修复的其他重要组成部分，但它们在这个过程中的作用方式尚不清楚。我们已将酵母MLH1-PMS1异二聚体纯化至接近均一状态，并研究了其对MSH2-MSH3与DNA错配结合的影响。MLH1-PMS1复合物自身对错配DNA没有亲和力，但它能极大地增强MSH2-MSH3的错配结合能力。
