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Molecular and Cellular Biology, May 2003, p. 3320-3328, Vol. 23, No. 9
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.9.3320-3328.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Dimerization of MLH1 and PMS2 Limits Nuclear Localization of MutL{alpha}

Xiaosheng Wu,1,2,3 Jeffrey L. Platt,1,3,4,5 and Marilia Cascalho1,3,4,5*

Transplantation Biology,1 Departments of Biochemistry and Molecular Biology,2 Immunology,4 Surgery,3 Pediatrics, Mayo Clinic, Rochester, Minnesota 559055

Received 4 November 2002/ Returned for modification 9 December 2002/ Accepted 31 January 2003

DNA mismatch repair maintains genomic stability by detecting and correcting mispaired DNA sequences and by signaling cell death when DNA repair fails. The mechanism by which mismatch repair coordinates DNA damage and repair with cell survival or death is not understood, but it suggests the need for regulation. Since the functions of mismatch repair are initiated in the nucleus, we asked whether nuclear transport of MLH1 and PMS2 is limiting for the nuclear localization of MutL{alpha} (the MLH1-PMS2 dimer). We found that MLH1 and PMS2 have functional nuclear localization signals (NLS) and nuclear export sequences, yet nuclear import depended on their C-terminal dimerization to form MutL{alpha}. Our studies are consistent with the idea that dimerization of MLH1 and PMS2 regulates nuclear import by unmasking the NLS. Limited nuclear localization of MutL{alpha} may thus represent a novel mechanism by which cells fine-tune mismatch repair functions. This mechanism may have implications in the pathogenesis of hereditary non-polyposis colon cancer.

* Corresponding author. Mailing address: Transplantation Biology Program, Mayo Clinic, Rochester, MN 55901. Phone: (507) 538-3711. Fax: (507) 284-4957. E-mail: cascalho.marilia{at}mayo.edu.

Molecular and Cellular Biology, May 2003, p. 3320-3328, Vol. 23, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.9.3320-3328.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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