ATM在DNA损伤同源重组修复中的调控作用。
The controlling role of ATM in homologous recombinational repair of DNA damage.
作者信息
Morrison C, Sonoda E, Takao N, Shinohara A, Yamamoto K, Takeda S
机构信息
Bayer Chair Department of Molecular Immunology and Allergology, Faculty of Medicine, Kyoto University, Japan.
出版信息
EMBO J. 2000 Feb 1;19(3):463-71. doi: 10.1093/emboj/19.3.463.
Abstract
The human genetic disorder ataxia telangiectasia (A-T), caused by mutation in the ATM gene, is characterized by chromosomal instability, radiosensitivity and defective cell cycle checkpoint activation. DNA double-strand breaks (dsbs) persist in A-T cells after irradiation, but the underlying defect is unclear. To investigate ATM's interactions with dsb repair pathways, we disrupted ATM along with other genes involved in the principal, complementary dsb repair pathways of homologous recombination (HR) or non-homologous end-joining (NHEJ) in chicken DT40 cells. ATM(-/-) cells show altered kinetics of radiation-induced Rad51 and Rad54 focus formation. Ku70-deficient (NHEJ(-)) ATM(-/-) chicken DT40 cells show radiosensitivity and high radiation-induced chromosomal aberration frequencies, while Rad54-defective (HR(-)) ATM(-/-) cells show only slightly elevated aberration levels after irradiation, placing ATM and HR on the same pathway. These results reveal that ATM defects impair HR-mediated dsb repair and may link cell cycle checkpoints to HR activation.
摘要
人类遗传性疾病共济失调毛细血管扩张症（A-T）由ATM基因的突变引起，其特征为染色体不稳定、辐射敏感性以及细胞周期检查点激活缺陷。照射后，DNA双链断裂（dsb）在A-T细胞中持续存在，但其潜在缺陷尚不清楚。为了研究ATM与dsb修复途径的相互作用，我们在鸡DT40细胞中破坏了ATM以及参与同源重组（HR）或非同源末端连接（NHEJ）这两种主要的、互补的dsb修复途径的其他基因。ATM（-/-）细胞显示出辐射诱导的Rad51和Rad54焦点形成的动力学改变。Ku70缺陷型（NHEJ（-））ATM（-/-）鸡DT40细胞表现出辐射敏感性和高辐射诱导的染色体畸变频率，而Rad54缺陷型（HR（-））ATM（-/-）细胞在照射后仅显示出略微升高的畸变水平，这表明ATM和HR处于同一途径。这些结果表明，ATM缺陷会损害HR介导的dsb修复，并可能将细胞周期检查点与HR激活联系起来。
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Disruption of ATM in p53-null cells causes multiple functional abnormalities in cellular response to ionizing radiation.在p53基因缺失的细胞中，ATM基因的破坏会导致细胞对电离辐射的反应出现多种功能异常。
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