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Research ArticleArticle

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

Dillon I. Beardsley, Wan-Ju Kim and Kevin D. Brown
Molecular Pharmacology October 2005, 68 (4) 1049-1060; DOI: https://doi.org/10.1124/mol.105.013888
Dillon I. Beardsley
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Wan-Ju Kim
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Kevin D. Brown
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Abstract

SN1-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.

  • Received April 18, 2005.
  • Accepted June 30, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 68 (4)
Molecular Pharmacology
Vol. 68, Issue 4
1 Oct 2005
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Research ArticleArticle

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

Dillon I. Beardsley, Wan-Ju Kim and Kevin D. Brown
Molecular Pharmacology October 1, 2005, 68 (4) 1049-1060; DOI: https://doi.org/10.1124/mol.105.013888

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Research ArticleArticle

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

Dillon I. Beardsley, Wan-Ju Kim and Kevin D. Brown
Molecular Pharmacology October 1, 2005, 68 (4) 1049-1060; DOI: https://doi.org/10.1124/mol.105.013888
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