Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Prog Mol Biol Transl Sci. 2012;110:41-70. doi: 10.1016/B978-0-12-387665-2.00003-1.
DNA mismatch repair enhances genomic stability by correcting errors that have escaped polymerase proofreading. One of the critical steps in DNA mismatch repair is discriminating the new from the parental DNA strand as only the former needs repair. In Escherichia coli, the latent endonuclease MutH carries out this function. However, most prokaryotes and all eukaryotes lack a mutH gene. MutL is a key component of this system that mediates protein-protein interactions during mismatch recognition, strand discrimination, and strand removal. Hence, it had long been thought that the primary function of MutL was coordinating sequential mismatch repair steps. However, recent studies have revealed that most MutL homologs from organisms lacking MutH encode a conserved metal-binding motif associated with a weak endonuclease activity. As MutL homologs bearing this activity are found only in organisms relying on MutH-independent DNA mismatch repair, this finding unveils yet another crucial function of the MutL protein at the strand discrimination step. In this chapter, we review recent functional and structural work aimed at characterizing the multiple functions of MutL and discuss how the endonuclease activity of MutL is regulated by other repair factors.
DNA 错配修复通过纠正逃脱聚合酶校对的错误来增强基因组稳定性。DNA 错配修复的关键步骤之一是区分新的和亲本 DNA 链，因为只有前者需要修复。在大肠杆菌中，潜伏的内切酶 MutH 执行此功能。然而，大多数原核生物和所有真核生物都缺乏 mutH 基因。MutL 是该系统的关键组成部分，它在错配识别、链区分和链去除过程中介导蛋白质-蛋白质相互作用。因此，长期以来，人们一直认为 MutL 的主要功能是协调顺序错配修复步骤。然而，最近的研究表明，缺乏 MutH 的生物体中的大多数 MutL 同源物都编码一个与弱内切酶活性相关的保守金属结合基序。由于具有这种活性的 MutL 同源物仅存在于依赖 MutH 独立的 DNA 错配修复的生物体中，这一发现揭示了 MutL 蛋白在链区分步骤中的另一个关键功能。在本章中，我们回顾了最近旨在表征 MutL 多种功能的功能和结构研究，并讨论了 MutL 的内切酶活性如何被其他修复因子调节。
