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Molecular and Cellular Biology, July 2004, p. 6430-6444, Vol. 24, No. 14
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.14.6430-6444.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

ATM-Mediated Stabilization of hMutL DNA Mismatch Repair Proteins Augments p53 Activation during DNA Damage

Yuhong Luo,1 Fang-Tsyr Lin,2 and Weei-Chin Lin1,2*

Division of Hematology and Oncology, Department of Medicine,1 Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294-33002

Received 20 January 2004/ Returned for modification 18 February 2004/ Accepted 26 April 2004

Human DNA mismatch repair (MMR) proteins correct DNA errors and regulate cellular response to DNA damage by signaling apoptosis. Mutations of MMR genes result in genomic instability and cancer development. Nonetheless, how MMR proteins are regulated has not yet been determined. While hMLH1, hPMS2, and hMLH3 are known to participate in MMR, the function of another member of MutL-related proteins, hPMS1, remains unclear. Here we show that DNA damage induces the accumulation of hPMS1, hPMS2, and hMLH1 through ataxia-telangiectasia-mutated (ATM)-mediated protein stabilization. The subcellular localization of PMS proteins is also regulated during DNA damage, which induces nuclear localization of hPMS1 and hPMS2 in an hMLH1-dependent manner. The induced levels of hMLH1 and hPMS1 are important for the augmentation of p53 phosphorylation by ATM in response to DNA damage. These observations identify hMutL proteins as regulators of p53 response and demonstrate for the first time a function of hMLH1-hPMS1 complex in controlling the DNA damage response.

* Corresponding author. Mailing address: 520A Wallace Tumor Institute, 1530 3rd Ave. S, Birmingham, AL 35294-3300. Phone: (205) 934-3979. Fax: (205) 975-6911. E-mail: wclin{at}uab.edu.

Molecular and Cellular Biology, July 2004, p. 6430-6444, Vol. 24, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.14.6430-6444.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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