The endonuclease domain of MutL interacts with the β sliding clamp

Mismatch repair corrects errors that have escaped polymerase proofreading enhancing replication fidelity by at least two orders of magnitude. The beta and PCNA sliding clamps increase the polymerase processivity during DNA replication and are important at several stages of mismatch repair. Both MutS and MutL, the two proteins that initiate the mismatch repair response, interact with beta. Binding of MutS to beta is important to recruit MutS and MutL to foci. Moreover, the endonuclease activity of human and yeast MutL alpha is stimulated by PCNA. However, the concrete functions of the processivity clamp in the repair steps preceding DNA resynthesis remain obscure. Here, we demonstrate that the C-terminal domain of MutL encompasses a bona fide beta-binding motif that mediates a weak, yet specific, interaction between the two proteins. Mutation of this conserved motif correlates with defects in mismatch repair, demonstrating that the direct interaction with beta is important for MutL function. The interaction between the C-terminal domain of MutL and beta is conserved in both Bacillus subtilis and Escherichia coli, but the repair defects associated with mutation of this beta-binding motif are more severe in the former, suggesting that this interaction may have a more prominent role in methyl-independent than methyl-directed mismatch repair systems. Together with previously published data, our work strongly suggests that beta may stimulate the endonuclease activity of MutL through its direct interaction with the C-terminal domain of MutL. (C) 2010 Elsevier B.V. All rights reserved.