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

Abstract

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.

We thank Bert Vogelstein for providing pBS-hPMS1 and William A. May for pSUPER plasmid. We thank Yosef Shiloh for ATM-reconstituted AT22IJE-T cells.

The work was supported by a General Motors Cancer Research Scholar Award (W.-C.L.), National Institutes of Health-National Cancer Institute grant K12 CA 7693705 (W.-C.L.), a UAB Avon/Breast Cancer SPORE Career Development Award (W.-C.L. and F.-T.L.), an HHMI Faculty Development Award (W.-C.L. and F.-T.L.), and grant CA100848 (F.-T.L.) from the National Institutes of Health.

All authors disclose that they have no financial interests that will pose a conflict of interest regarding this article.