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N-Methyl-N'-nitro-N-nitrosoguanidine Activates Cell-Cycle Arrest through Distinct Mechanisms Activated in a Dose-Dependent Manner

Department of Biochemistry and Molecular Biology and the UF Shands Cancer Center, University of Florida College of Medicine, Gainesville, Florida

S_N1-alkylating agents, such as the mutagenic and cytotoxic drug N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), robustly activate the DNA damage-responsive G₂ checkpoint. Establishment of this checkpoint is dependent on a functional mismatch repair (MMR) system; however, exposure to high doses of MNNG overrides the requirement for MMR to trigger G₂ arrest. In addition, unlike moderate-dose exposure, in which the G₂ checkpoint is attenuated in ataxia-telangiectasia, mutated (ATM)-deficient cells, high-dose MNNG treatment activates G₂ arrest through an ATM-independent mechanism. We document that this arrest is sensitive to the pharmacological agents caffeine and 7-hydroxystaurosporine (UCN-01) that inhibit the checkpoint kinases ATM/ATM and Rad-3–related (ATR) and Chk1/Chk2, respectively. Furthermore, these agents block inactivation of the cell-cycle regulatory molecules Cdc25C and Cdc2, establishing the downstream mechanism through which high-dose MNNG establishes G₂ arrest. Activation of both Chk2 and Chk1 was independent of ATM and MMR in response to high-dose MNNG, unlike the response to moderate doses of this drug. Chk2 was found to be dispensable for cell-cycle arrest in response to high-dose MNNG treatment; however, ATR deficiency and decreased Chk1 expression forced by RNA interference resulted in diminished checkpoint response. These results indicate that MNNG activates the G₂ checkpoint through different mechanisms activated in a dose-dependent fashion.

Address correspondence to: Dr. K. D. Brown, Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, 1600 SW Archer Road, Box 100245, Gainesville, FL 32611. E-mail: kdbrown1{at}ufl.edu

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