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MBC in Press, published online ahead of print January 12, 2005
Mol. Biol. Cell 10.1091/mbc.E04-02-0089

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Submitted on February 3, 2004
Revised on December 13, 2004
Accepted on December 21, 2004

Methylator-induced, Mismatch Repair-dependent G2 Arrest Is Activated through Chk1 and Chk2

Aaron W. Adamson,*{dagger}{ddagger} Dillon I. Beardsley,*{dagger}{sect} Wan-Ju Kim,{dagger}{sect} Yajuan Gao,|| R. Baskaran,|| and Kevin D. Brown{sect}

*Department of Biochemistry and Molecular Biology and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112; {sect}Department of Biochemistry and Molecular Biology and the Shands Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610; ||Department of Molecular Genetics and Biochemistry, University of Pittsburgh Medical Center, Pittsburgh, PA 15261

Monitoring Editor: Tony Hunter

SN1 DNA methylating agents such as the nitrosourea N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) elicit a G2/M checkpoint response via a mismatch repair (MMR) system-dependent mechanism; however, the exact nature of the mechanism governing MNNG-induced G2/M arrest and how MMR mechanistically participates in this process is unknown. Here we show that MNNG exposure results in activation of the cell cycle checkpoint kinases ATM, Chk1 and Chk2, each of which has been implicated in the triggering of the G2/M checkpoint response. We document that MNNG induces a robust, dose-dependent G2 arrest in MMR and ATM-proficient cells while this response is abrogated in MMR-deficient cells and attenuated in ATM deficient cells treated with moderate doses of MNNG. Pharmacologic and RNA interference approaches indicated that Chk1 and Chk2 are both required components for normal MNNG induced G2 arrest. MNNG-induced nuclear exclusion of the cell cycle regulatory phosphatase Cdc25C occurred in a MMR-dependent manner and was compromised in cells lacking ATM. Finally, both Chk1 and Chk2 interact with the MMR protein MSH2 and this interaction is enhanced following MNNG exposure, supporting the notion that the MMR system functions as a molecular scaffold at the sites of DNA damage that facilitates activation of these kinases.

{dagger}These authors contributed equally to this work.

{ddagger}Present address: Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808.

Corresponding author. E-mail: kdbrown1{at}ufl.edu




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