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J. Biol. Chem., Vol. 282, Issue 12, 9279-9287, March 23, 2007

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Bcl2 Impedes DNA Mismatch Repair by Directly Regulating the hMSH2-hMSH6 Heterodimeric Complex^*

From the Departments of Medicine and Anatomy & Cell Biology, Shands Cancer Center, University of Florida, Gainesville, Florida 32610-3633

Bcl2 has been reported to suppress DNA mismatch repair (MMR) with promotion of mutagenesis, but the mechanism(s) is not fully understood. MutS is the hMSH2-hMSH6 heterodimer that primarily functions to correct mutations that escape the proofreading activity of DNA polymerase. Here we have discovered that Bcl2 potently suppresses MMR in association with decreased MutS activity and increased mutagenesis. Exposure of cells to nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone results in accumulation of Bcl2 in the nucleus, which interacts with hMSH6 but not hMSH2 via its BH4 domain. Deletion of the BH4 domain from Bcl2 abrogates the ability of Bcl2 to interact with hMSH6 and is associated with enhanced MMR efficiency and decreased mutation frequency. Overexpression of Bcl2 reduces formation of the hMSH2-hMSH6 complex in cells, and purified Bcl2 protein directly disrupts the hMSH2-hMSH6 complex and suppresses MMR in vitro. Importantly, depletion of endogenous Bcl2 by RNA interference enhances formation of the hMSH2-hMSH6 complex in association with increased MMR and decreased mutagenesis. Thus, Bcl2 suppression of MMR may occur in a novel mechanism by directly regulating the heterodimeric hMSH2-hMSH6 complex, which potentially contributes to genetic instability and carcinogenesis.

Received for publication, September 5, 2006 , and in revised form, January 26, 2007.

^* This work was supported by NCI, National Institutes of Health Grant R01 CA112183, by a Flight Attendant Medical Research Institute Clinical Innovator Award, and a Fu Rong Scholarship (to X. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Department of Surgery, Xiangya Hospital, Central South University, Changsha, China.

² To whom correspondence should be addressed: Shands Cancer Ctr., University of Florida 1376 Mowry Rd., Cancer/Genetics Research Complex, Rm. 262, P.O. Box 103633, Gainesville, FL 32610-3633. Tel.: 352-273-8170; Fax: 352-273-8285; E-mail: xdeng{at}ufl.edu.

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