Abstract
BackgroundThe MYC protein controls cellular functions such as differentiation, proliferation, and apoptosis. In response to genotoxic agents, cells overexpressing MYC undergo apoptosis. However, the MYC-regulated effectors acting upstream of the mitochondrial apoptotic pathway are still unknown.Principal FindingsIn this study, we demonstrate that expression of Myc is required to activate the Ataxia telangiectasia mutated (ATM)-dependent DNA damage checkpoint responses in rat cell lines exposed to ionizing radiation (IR) or the bacterial cytolethal distending toxin (CDT). Phosphorylation of the ATM kinase and its downstream effectors, such as histone H2AX, were impaired in the myc null cell line HO15.19, compared to the myc positive TGR-1 and HOmyc3 cells. Nuclear foci formation of the Nijmegen Breakage Syndrome (Nbs) 1 protein, essential for efficient ATM activation, was also reduced in absence of myc. Knock down of the endogenous levels of MYC by siRNA in the human cell line HCT116 resulted in decreased ATM and CHK2 phosphorylation in response to irradiation. Conversely, cell death induced by UV irradiation, known to activate the ATR-dependent checkpoint, was similar in all the cell lines, independently of the myc status.ConclusionThese data demonstrate that MYC contributes to the activation of the ATM-dependent checkpoint responses, leading to cell death in response to specific genotoxic stimuli.
Highlights
The MYC transcription factor regulates a wide variety of cellular functions such as proliferation, differentiation, cellular motility, and apoptosis
We demonstrate that myc deletion impairs activation of the Ataxia telangiectasia mutated (ATM) dependent DNA damage checkpoint responses in cells exposed to ionizing radiation (IR) or the cytolethal distending toxin (CDT), including impaired phosphorylation of ATM and its downstream target H2AX, and reduced nuclear foci formation of the MRN complex
To identify the Myc-regulated effectors acting upstream of the mitochondrial apoptotic pathway, we used the Rat1 fibroblasts TGR-1 expressing physiological levels of Myc, the isogenic myc null HO15.19 cell line, and the HOmyc3 cell line, where expression of the murine myc gene was reconstituted into the HO15.19 background [27]
Summary
The MYC transcription factor regulates a wide variety of cellular functions such as proliferation, differentiation, cellular motility, and apoptosis (reviewed in [1]). The oncogenic capacity of MYC is dependent on its ability to regulate expression of genes that enhance cell proliferation (e.g up-regulation of cyclin D2, Cdk and E2F) or suppress cell cycle arrest (e.g. down-regulation of p21CIP1 or p15INK4B, reviewed in [5]), but it may contribute to tumorigenesis by induction of DNA damage, and consequent genomic instability [6,7,8,9] Stress signals, such as growth factor deprivation, hypoxia, and exposure to genotoxic agents trigger MYC dependent apoptosis [10,11]. The MYC-regulated effectors acting upstream of the mitochondrial apoptotic pathway are still unknown
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