Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
G3 (Bethesda). 2013 Jun 21;3(6):1043-8. doi: 10.1534/g3.113.006312.
Using Drosophila as a model system, we identified a stringent requirement for the conserved function of Ataxia Telangiectasia Mutated (ATM) in telomere protection during early embryonic development. Animals homozygous for a hypomorphic mutation in atm develop normally with minimal telomere dysfunction. However, mutant females produce inviable embryos that succumb to mitotic failure caused by covalent fusions of telomeric DNA. Interestingly, although the atm mutation encodes a premature stop codon, it must not have eliminated the production of the mutant protein, and the mutant protein retains kinase activity upon DNA damage. Moreover, although the embryonic phenotype of this mutation resembles that of hypomorphic mutations in the MRN complex, the function of MRN appears normal in the atm embryos. In contrast, there is a prominent reduction of the level of HipHop, an essential member of the Drosophila capping complex. How ATM functions in telomere protection remains poorly understood. The amenability of Drosophila embryos to molecular and biochemical investigations ensures that this newly identified mutation will facilitate future studies of ATM in telomere maintenance.
利用果蝇作为模型系统，我们发现 Ataxia Telangiectasia Mutated（ATM）在早期胚胎发育过程中保护端粒的保守功能有着严格的需求。在 atm 中存在功能减弱突变的动物能够正常发育，端粒功能障碍极小。然而，突变雌性产生的胚胎无法存活，因为端粒 DNA 的共价融合导致有丝分裂失败。有趣的是，尽管 atm 突变编码了一个过早的终止密码子，但它一定没有完全消除突变蛋白的产生，并且突变蛋白在 DNA 损伤后仍然保留激酶活性。此外，尽管这种突变的胚胎表型类似于 MRN 复合物中的功能减弱突变，但 atm 胚胎中的 MRN 功能似乎正常。相比之下，果蝇封端复合物的一个必需成员 HipHop 的水平显著降低。ATM 如何在端粒保护中发挥作用仍知之甚少。果蝇胚胎易于进行分子和生化研究，这确保了这个新发现的突变将有助于未来 ATM 在端粒维持方面的研究。
