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Originally published In Press as doi:10.1074/jbc.M005377200 on August 22, 2000

J. Biol. Chem., Vol. 275, Issue 46, 36256-36262, November 17, 2000
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Nuclear Translocation of Mismatch Repair Proteins MSH2 and MSH6 as a Response of Cells to Alkylating Agents*

Markus Christmann and Bernd KainaDagger

From the Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany

Mammalian mismatch repair has been implicated in mismatch correction, the prevention of mutagenesis and cancer, and the induction of genotoxicity and apoptosis. Here, we show that treatment of cells specifically with agents inducing O6-methylguanine in DNA, such as N-methyl-N'-nitro-N-nitrosoguanidine and N-methyl-N-nitrosourea, elevates the level of MSH2 and MSH6 and increases GT mismatch binding activity in the nucleus. This inducible response occurs immediately after alkylation, is long-lasting and dose-dependent, and results from translocation of the preformed MutSalpha complex (composed of MSH2 and MSH6) from the cytoplasm into the nucleus. It is not caused by an increase in MSH2 gene activity. Cells expressing the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), thus having the ability to repair O6-methylguanine, showed no translocation of MutSalpha , whereas inhibition of MGMT by O6-benzylguanine provoked the translocation. The results demonstrate that O6-methylguanine lesions are involved in triggering nuclear accumulation of MSH2 and MSH6. The finding that treatment of cells with O6-methylguanine-generating mutagens results in an increase of MutSalpha and GT binding activity in the nucleus indicates a novel type of genotoxic stress response.

* This work was supported by the Deutsche Forschungsgemeinschaft (SFB 519/B4).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. Tel.: 0049-6131-393-3246; Fax: 0049-6131-393-3421; E-mail: Kaina@mail.uni-mainz.de.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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