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FEBS J. 2013 Jul;280(14):3467-79. doi: 10.1111/febs.12344. Epub 2013 Jun 18.

MutS stimulates the endonuclease activity of MutL in an ATP-hydrolysis-dependent manner.

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  • 1Department of Biological Sciences, Graduate School of Science, Osaka University, Suita, Osaka, Japan.


In the initial steps of DNA mismatch repair, MutS recognizes a mismatched base and recruits the latent endonuclease MutL onto the mismatch-containing DNA in concert with other proteins. MutL then cleaves the error-containing strand to introduce an entry point for the downstream excision reaction. Because MutL has no intrinsic ability to recognize a mismatch and discriminate between newly synthesized and template strands, the endonuclease activity of MutL is strictly regulated by ATP-binding in order to avoid nonspecific degradation of the genomic DNA. However, the activation mechanism for its endonuclease activity remains unclear. In this study, we found that the coexistence of a mismatch, ATP and MutS unlocks the ATP-binding-dependent suppression of MutL endonuclease activity. Interestingly, ATPase-deficient mutants of MutS were unable to activate MutL. Furthermore, wild-type MutS activated ATPase-deficient mutants of MutL less efficiently than wild-type MutL. We concluded that ATP hydrolysis by MutS and MutL is involved in the mismatch-dependent activation of MutL endonuclease activity.


ATP hydrolysis; DNA mismatch repair; MutL; MutS; endonuclease activity

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