Centrosome amplification induced by DNA damage occurs during a prolonged G2 phase and involves ATM
Centrosome amplification induced by DNA damage occurs during a prolonged G2 phase and involves ATM
复制标题
DOI：
10.1038/sj.emboj.7600393
复制
发表时间：
2004-09-29
期刊：
影响因子：
11.4
通讯作者：
Morrison, C
中科院分区：
文献类型：
--
作者：
Dodson, H;Bourke, E;Morrison, C
中心体是体细胞中主要的微管组织中心。异常的中心体数量在肿瘤中很常见，并且发生在伽马射线照射后和DNA修复基因突变的细胞中。为了研究DNA损伤如何引起中心体扩增，我们检查了条件性缺乏Rad 51重组酶的细胞，从而引起高水平的自发DNA损伤。Rad 51缺陷细胞停滞在G2期，并形成额外的功能中心体，通过光学和连续切片电子显微镜评估。这种中心体扩增在没有额外的DNA复制轮的情况下发生，并且不是胞质分裂失败的结果。咖啡因或渥曼青霉素处理的G2-to-M检查点覆盖强烈降低了DNA损伤诱导的中心体扩增。辐射诱导的中心体扩增增强Rad 54中断。ATM的基因靶向减少，但没有废除，中心体扩增诱导的DNA损伤的Rad 51和Rad 54敲除模型，证明ATM依赖和非依赖的组件的DNA损伤诱导的G2期中心体扩增。我们的数据表明，DNA损伤诱导的中心体扩增作为一种机制，以确保逃避DNA损伤或纺锤体组装检查点的细胞死亡。
Centrosomes are the principal microtubule organising centres in somatic cells. Abnormal centrosome number is common in tumours and occurs after gamma-irradiation and in cells with mutations in DNA repair genes. To investigate how DNA damage causes centrosome amplification, we examined cells that conditionally lack the Rad51 recombinase and thereby incur high levels of spontaneous DNA damage. Rad51-deficient cells arrested in G2 phase and formed supernumerary functional centrosomes, as assessed by light and serial section electron microscopy. This centrosome amplification occurred without an additional DNA replication round and was not the result of cytokinesis failure. G2-to-M checkpoint over-ride by caffeine or wortmannin treatment strongly reduced DNA damage-induced centrosome amplification. Radiation-induced centrosome amplification was potentiated by Rad54 disruption. Gene targeting of ATM reduced, but did not abrogate, centrosome amplification induced by DNA damage in both the Rad51 and Rad54 knockout models, demonstrating ATM-dependent and -independent components of DNA damage-inducible G2-phase centrosome amplification. Our data suggest DNA damage-induced centrosome amplification as a mechanism for ensuring death of cells that evade the DNA damage or spindle assembly checkpoints.