Song Young-Han, Mirey Gladys, Betson Martha, Haber Daniel A, Settleman Jeffrey
Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th St., Charlestown, MA 02129, USA.
Curr Biol. 2004 Aug 10;14(15):1354-9. doi: 10.1016/j.cub.2004.06.064.
Cells of metazoan organisms respond to DNA damage by arresting their cell cycle to repair DNA, or they undergo apoptosis. Two protein kinases, ataxia-telangiectasia mutated (ATM) and ATM and Rad-3 related (ATR), are sensors for DNA damage. In humans, ATM is mutated in patients with ataxia-telangiectasia (A-T), resulting in hypersensitivity to ionizing radiation (IR) and increased cancer susceptibility. Cells from A-T patients exhibit chromosome aberrations and excessive spontaneous apoptosis. We used Drosophila as a model system to study ATM function. Previous studies suggest that mei-41 corresponds to ATM in Drosophila; however, it appears that mei-41 is probably the ATR ortholog. Unlike mei-41 mutants, flies deficient for the true ATM ortholog, dATM, die as pupae or eclose with eye and wing abnormalities. Developing larval discs exhibit substantially increased spontaneous chromosomal telomere fusions and p53-dependent apoptosis. These developmental phenotypes are unique to dATM, and both dATM and mei-41 have temporally distinct roles in G2 arrest after IR. Thus, ATM and ATR orthologs are required for different functions in Drosophila; the developmental defects resulting from absence of dATM suggest an important role in mediating a protective checkpoint against DNA damage arising during normal cell proliferation and differentiation.
后生动物的细胞通过停滞细胞周期来修复DNA，或者经历凋亡来响应DNA损伤。两种蛋白激酶，共济失调毛细血管扩张症突变蛋白（ATM）和ATM与Rad-3相关蛋白（ATR），是DNA损伤的感受器。在人类中，共济失调毛细血管扩张症（A-T）患者的ATM发生突变，导致对电离辐射（IR）敏感以及癌症易感性增加。A-T患者的细胞表现出染色体畸变和过度的自发凋亡。我们使用果蝇作为模型系统来研究ATM的功能。先前的研究表明，mei-41在果蝇中对应于ATM；然而，mei-41似乎可能是ATR的直系同源物。与mei-41突变体不同，缺乏真正的ATM直系同源物dATM的果蝇在蛹期死亡或羽化时出现眼睛和翅膀异常。发育中的幼虫盘表现出自发染色体端粒融合和p53依赖性凋亡显著增加。这些发育表型是dATM特有的，并且dATM和mei-41在IR后的G2期停滞中具有时间上不同的作用。因此，ATM和ATR直系同源物在果蝇中具有不同的功能；缺乏dATM导致的发育缺陷表明其在介导针对正常细胞增殖和分化过程中产生的DNA损伤的保护性检查点中起重要作用。
