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Differentiation-Induced Radioresistance in Muscle Cells

机译：分化诱导的肌细胞放射抗性

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DNA damage induces cell cycle arrest and DNA repair or apoptosis in proliferating cells. Terminally differentiated cells are permanently withdrawn from the cell cycle and partly resistant to apoptosis. To investigate the effects of genotoxic agents in postmitotic cells, we compared DNA damage-activated responses in mouse and human proliferating myoblasts and their differentiated counterparts, the myotubes. DNA double-strand breaks caused by ionizing radiation (IR) induced rapid activating autophosphorylation of ataxia-teleangiectasia-mutated (ATM), phosphorylation of histone H2AX, recruitment of repair-associated proteins MRE11 and Nbs1, and activation of Chk2 in both myoblasts and myotubes. However, IR-activated, ATM-mediated phosphorylation of p53 at serine 15 (human) or 18 (mouse) [Ser15(h)/18(m)], and apoptosis occurred in myoblasts but was impaired in myotubes. This phosphorylation could be enforced in myotubes by the anthracycline derivative doxorubicin, leading to selective activation of proapoptotic genes. Unexpectedly, the abundance of autophosphorylated ATM was indistinguishable after exposure of myotubes to IR (10 Gy) or doxorubicin (1 μM/24 h) despite efficient phosphorylation of p53 Ser15(h)/18(m), and apoptosis occurred only in response to doxorubicin. These results suggest that radioresistance in myotubes might reflect a differentiation-associated, pathway-selective blockade of DNA damage signaling downstream of ATM. This mechanism appears to preserve IR-induced activation of the ATM-H2AX-MRE11/Rad50/Nbs1 lesion processing and repair pathway yet restrain ATM-p53-mediated apoptosis, thereby contributing to life-long maintenance of differentiated muscle tissues.
机译：DNA损伤诱导增殖细胞中的细胞周期停滞和DNA修复或凋亡。终末分化的细胞从细胞周期中永久退出，部分抵抗凋亡。为了研究遗传毒性剂在有丝分裂后细胞中的作用，我们比较了小鼠和人类增殖的成肌细胞及其分化的成肌细胞中的DNA损伤激活反应。由电离辐射（IR）引起的DNA双链断裂引起共济失调-电血管扩张突变（ATM）的快速激活自磷酸化，组蛋白H2AX的磷酸化，修复相关蛋白MRE11和Nbs1的募集以及成肌细胞和肌管中Chk2的激活。然而，在丝氨酸15（人）或18（小鼠）[Ser15（h）/ 18（m）]处，IR激活的ATM介导的p53磷酸化[Ser15（h）/ 18（m）]，凋亡发生在成肌细胞中，但在肌管中受损。蒽环类衍生物阿霉素可在肌管中增强这种磷酸化作用，从而导致促凋亡基因的选择性激活。出乎意料的是，尽管p53 Ser15（h）/ 18（m）有效磷酸化，但肌管暴露于IR（10 Gy）或阿霉素（1μM/ 24 h）后，自磷酸化ATM的丰度仍无法区分。阿霉素。这些结果表明，肌管中的放射抗性可能反映了ATM下游DNA损伤信号的分化相关的，途径选择性的阻断。该机制似乎保留了IR诱导的ATM-H2AX-MRE11 / Rad50 / Nbs1损伤处理和修复途径的激活，但仍抑制了ATM-p53介导的细胞凋亡，从而有助于终生维持分化的肌肉组织。

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