The functions of MutL in mismatch repair: the power of multitasking

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.