Transient ATM kinase inhibition disrupts DNA damage-induced sister chromatid exchange.
Transient ATM kinase inhibition disrupts DNA damage-induced sister chromatid exchange.
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DOI：
10.1126/scisignal.2000758
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发表时间：
2010-06-01
影响因子：
7.3
通讯作者：
Bakkenist CJ
中科院分区：
文献类型：
--
作者：
White JS;Choi S;Bakkenist CJ
由于编码 ATM 的基因发生突变（共济失调毛细血管扩张突变），来自共济失调毛细血管扩张 (A-T) 患者的细胞表现出有缺陷的细胞周期检查点。暴露于电离辐射 (IR) 后，A-T 细胞对 IR 诱导的细胞损伤表现出敏感性，导致染色体畸变和细胞死亡增加（放射敏感性）。 ATM 是激酶家族的成员，可响应 DNA 损伤而被激活。我们发现，即使在细胞照射后 15 分钟开始短暂抑制 ATM 激酶 1 小时，也会导致持久性染色体畸变的积累并增加细胞死亡。使用 DNA-PK（DNA 依赖性蛋白激酶）（另一种参与 DNA 损伤响应的激酶）和 ATM 的可逆抑制剂，我们发现这两种激酶通过不同的 DNA 修复机制发挥作用：ATM 通过涉及姐妹染色单体交换 (SCE) 的机制解决 DNA 损伤，而 DNA-PK 通过非同源末端连接发挥作用。此外，由于DNA损伤诱导的SCE发生在缺乏功能性ATM蛋白的A-T成纤维细胞中，而ATM激酶抑制剂对A-T成纤维细胞中DNA损伤诱导的SCE没有影响，因此我们发现短期抑制ATM激酶活性和适应ATM蛋白破坏的后果是不同的。这表明 A-T 成纤维细胞已经适应了 ATM 的丧失，并具有启动 SCE 的替代机制。
Cells derived from ataxia telangiectasia (A-T) patients exhibit defective cell cycle checkpoints because of mutations in the gene encoding ATM (ataxia telangiectasia mutated). After exposure to ionizing radiation (IR), A-T cells exhibit sensitivity to IR-induced cellular damage that results in increased chromosome aberrations and cell death (radiosensitivity). ATM is a member of a family of kinases that become activated in response to DNA damage. We showed that even transient inhibition of ATM kinase for 1 hour, initiated 15 minutes after cellular irradiation, resulted in an accumulation of persistent chromosome aberrations and increased cell death. Using reversible inhibitors of DNA-PK (DNA-dependent protein kinase), another kinase involved in responding to DNA damage, and ATM, we showed that these two kinases acted through distinct DNA repair mechanisms: ATM resolved DNA damage through a mechanism involving sister chromatid exchange (SCE), whereas DNA-PK acted through nonhomologous end joining. Furthermore, because DNA damage–induced SCE occurred in A-T fibroblasts that lack functional ATM protein, and the inhibitors of ATM kinase had no effect on DNA damage–induced SCE in A-T fibroblasts, we showed that the consequences of short-term inhibition of the kinase activity of ATM and adaptation to ATM protein disruption were distinct. This suggests that A-T fibroblasts have adapted to the loss of ATM and have alternative mechanisms to initiate SCE.
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影响因子：
21.3
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