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Nucleic Acids Research Advance Access published online on May 27, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp380
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleic Acid Enzymes

Physical and functional interactions between Escherichia coli MutL and the Vsr repair endonuclease

Roger J. Heinze1, Luis Giron-Monzon1, Alexandra Solovyova2, Sarah L. Elliot2, Sven Geisler1, Claire G. Cupples3, Bernard A. Connolly2 and Peter Friedhoff1,*

1Institut für Biochemie, Justus-Liebig-Universität, D-35392 Giessen, Germany, 2Institute for Cell and Molecular Biosciences (ICaMB), University of Newcastle, Newcastle upon Tyne NE2 4HH, UK and 3Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, V8W 3P6, Canada

*To whom correspondence should be addressed. Tel: +49 641 9935407; Fax: +49 641 9935409; Email: friedhoff{at}chemie.bio.uni-giessen.de

Received February 9, 2009. Revised April 16, 2009. Accepted April 27, 2009.

DNA mismatch repair (MMR) and very-short patch (VSP) repair are two pathways involved in the repair of T:G mismatches. To learn about competition and cooperation between these two repair pathways, we analyzed the physical and functional interaction between MutL and Vsr using biophysical and biochemical methods. Analytical ultracentrifugation reveals a nucleotide-dependent interaction between Vsr and the N-terminal domain of MutL. Using chemical crosslinking, we mapped the interaction site of MutL for Vsr to a region between the N-terminal domains similar to that described before for the interaction between MutL and the strand discrimination endonuclease MutH of the MMR system. Competition between MutH and Vsr for binding to MutL resulted in inhibition of the mismatch-provoked MutS- and MutL-dependent activation of MutH, which explains the mutagenic effect of Vsr overexpression. Cooperation between MMR and VSP repair was demonstrated by the stimulation of the Vsr endonuclease in a MutS-, MutL- and ATP-hydrolysis-dependent manner, in agreement with the enhancement of VSP repair by MutS and MutL in vivo. These data suggest a mobile MutS–MutL complex in MMR signalling, that leaves the DNA mismatch prior to, or at the time of, activation of downstream effector molecules such as Vsr or MutH.


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