Saccharomyces cerevisiae Msh2-Msh3 acts in repair of base-base mispairs
Saccharomyces cerevisiae Msh2-Msh3 acts in repair of base-base mispairs
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DOI：
10.1128/mcb.00855-07
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发表时间：
2007-09-01
影响因子：
5.3
通讯作者：
Kolodner, Richard D.
中科院分区：
文献类型：
--
作者：
Harrington, Jill A.;Kolodner, Richard D.
DNA错配修复被认为通过两个子途径起作用，涉及通过Msh 2-Msh 6异二聚体识别碱基-碱基和插入/缺失错配以及通过Msh 2-Msh 3异二聚体识别插入/缺失错配。在这里，通过遗传和生物化学的方法，我们描述了一个以前未确定的作用MSH 2-MSH 3异二聚体在识别碱基-碱基错配和抑制同源介导的重复和缺失突变。与野生型相比，酿酒酵母msh 3突变体的CAN 1正向突变试验未显示出碱基置换突变率的增加，但确实显示出碱基置换突变谱的改变，包括从GC到CG和从AT到TA的碱基对变化的积累增加; msh 3突变体还积累了同源介导的重复和缺失突变。mlh 3突变体的突变谱与msh 3突变体的突变谱一致，表明Mlh 1-Mlh 3异源二聚体也可能在碱基-碱基错配的修复和抑制同源介导的重复和缺失突变中发挥作用。用纯化的Msh 2-Msh 3和源自发现在体内突变的CAN 1序列的DNA底物进行的错配结合分析证明，Msh 2-Msh 3表现出与特异性碱基-碱基错配的稳健结合，这与功能性错配结合一致。
DNA mismatch repair is thought to act through two subpathways involving the recognition of base-base and insertion/deletion mispairs by the Msh2-Msh6 heterodimer and the recognition of insertion/deletion mispairs by the Msh2-Msh3 heterodimer. Here, through genetic and biochemical approaches, we describe a previously unidentified role of the Msh2-Msh3 heterodimer in the recognition of base-base mispairs and the suppression of homology-mediated duplication and deletion mutations. Saccharomyces cerevisiae msh3 mutants did not show an increase in the rate of base substitution mutations by the CAN1 forward mutation assay compared to the rate for the wild type but did show an altered spectrum of base substitution mutations, including an increased accumulation of base pair changes from GC to CG and from AT to TA; msh3 mutants also accumulated homology-mediated duplication and deletion mutations. The mutation spectrum of mlh3 mutants paralleled that of msh3 mutants, suggesting that the Mlh1-Mlh3 heterodimer may also play a role in the repair of base-base mispairs and in the suppression of homology-mediated duplication and deletion mutations. Mispair binding analysis with purified Msh2-Msh3 and DNA substrates derived from CAN1 sequences found to be mutated in vivo demonstrated that Msh2-Msh3 exhibited robust binding to specific base-base mispairs that was consistent with functional mispair binding.