Nucleic Acids Research, 2002, Vol. 30, No. 9 1959-1966
© 2002 Oxford University Press
Phosphorylation of mismatch repair proteins MSH2 and MSH6 affecting MutS
mismatch-binding activity
Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany
Mismatch repair (MMR) is involved in the removal of mispaired bases from DNA and thus plays an important role in the maintenance of genomic stability and the prevention of mutations and cancer. Moreover, MMR triggers genotoxicity and apoptosis upon processing of DNA lesions such as O6-methylguanine. Whereas the enzymology of MMR has been elucidated in great detail, only limited data are available concerning its regulation. Here we show that the major mismatch-binding proteins MSH2 and MSH6, forming the MutS
complex, are phosphorylated in vitro by protein kinase C and casein kinase II, but not by protein kinase A. Phosphorylation of MSH2 and MSH6 was also found within the cell, with MSH6 being more extensively phosphorylated than MSH2. Lack of MSH2 and MSH6 phosphorylation in vivo due to phosphate depletion, kinase inhibition (by H7 and quercetin) and treatment with phosphatases (CIP, SAP and 
-PPase) significantly reduced mismatch-binding activity of MutS. It also prevented methylation-induced nuclear translocation of the repair complex, indicating that nuclear translocation of MutS upon mutagen treatment is dependent on protein phosphorylation. The finding that MSH2 and MSH6 are subject to phosphorylation resulting in increased mismatch binding by MutS indicates a novel type of post-translational regulation of MMR which might be involved in the response of cells to genotoxic stress.
* To whom correspondence should be addressed. Tel: +49 6131 393 3246; Fax: +49 6131 393 3421; Email: kaina{at}mail.uni-mainz.de
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