N-methyl-N'-nitro-N-nitrosoguanidine activates cell-cycle arrest through distinct mechanisms activated in a dose-dependent manner - PubMed (original) (raw)
. 2005 Oct;68(4):1049-60.
doi: 10.1124/mol.105.013888. Epub 2005 Jun 30.
Affiliations
- PMID: 15994368
- DOI: 10.1124/mol.105.013888
N-methyl-N'-nitro-N-nitrosoguanidine activates cell-cycle arrest through distinct mechanisms activated in a dose-dependent manner
Dillon I Beardsley et al. Mol Pharmacol. 2005 Oct.
Abstract
S(N)1-alkylating agents, such as the mutagenic and cytotoxic drug N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), robustly activate the DNA damage-responsive G(2) 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 G(2) arrest. In addition, unlike moderate-dose exposure, in which the G(2) checkpoint is attenuated in ataxia-telangiectasia, mutated (ATM)-deficient cells, high-dose MNNG treatment activates G(2) 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 G(2) 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 G(2) checkpoint through different mechanisms activated in a dose-dependent fashion.
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