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Nucleic Acids Research Advance Access published online on June 12, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm409
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© 2007 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

Multiple functions for the N-terminal region of Msh6

Alan B. Clark1,2, Leesa Deterding1, Kenneth B. Tomer1 and Thomas A. Kunkel1,2,*

1Laboratory of Structural Biology and 2Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

*To whom correspondence should be addressed. Tel: 919-541-2644; Fax: 919-541-7613; Email: kunkel{at}niehs.nih.gov

Received March 3, 2007. Revised May 2, 2007. Accepted May 2, 2007.

The eukaryotic mismatch repair protein Msh6 shares five domains in common with other MutS members. However, it also contains several hundred additional residues at its N-terminus. A few of these residues bind to PCNA, but the functions of the other amino acids in the N-terminal region (NTR) are unknown. Here we demonstrate that the Msh6 NTR binds to duplex DNA in a salt-sensitive, mismatch-independent manner. Partial proteolysis, DNA affinity chromatography and mass spectrometry identified a fragment comprised of residues 228–299 of yeast Msh6 that binds to DNA and is rich in positively charged residues. Deleting these residues, or replacing lysines and arginines with glutamate, reduces DNA binding in vitro and elevates spontaneous mutation rates and resistance to MNNG treatment in vivo. Similar in vivo defects are conferred by alanine substitutions in a highly conserved motif in the NTR that immediately precedes domain I of MutS proteins, the domain that interacts with mismatched DNA. These data suggest that, in addition to PCNA binding, DNA binding and possibly other functions in the amino terminal region of Msh6 are important for eukaryotic DNA mismatch repair and cellular response to alkylation damage.


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