The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis
The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis
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DOI：
10.1038/35071124
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发表时间：
2001-04-12
期刊：
影响因子：
64.8
通讯作者：
Lukas, J
中科院分区：
文献类型：
--
作者：
Falck, J;Mailand, N;Lukas, J
当暴露于电离辐射（IR）时，真核细胞激活检查点途径以延迟细胞周期的进展（1-3）。IR诱导的S期检查点的缺陷导致“抗辐射DNA合成”，这是一种在患有共济失调-毛细血管扩张症的癌症易感患者中发现的现象，共济失调-毛细血管扩张症是一种由ATM基因突变引起的疾病（4-6）。Cdc 25 A磷酸酶（7）激活DNA合成所需的细胞周期蛋白依赖性激酶2（Cdk 2）（8，9），但在DNA损伤（10）或复制停滞（11）时降解。在这里，我们报告了ATM，检查点信号激酶Chk 2/Cds 1（Chk 2）（12）和Cdc 25 A之间的功能联系，并暗示这种机制在控制S期检查点。我们发现，红外线诱导的破坏Cdc 25 A需要ATM和Chk 2介导的磷酸化Cdc 25 A的丝氨酸123。IR诱导的Cdc 25 A蛋白的丢失阻止Cdk 2的去磷酸化，并导致DNA复制的瞬时阻断。我们还表明，肿瘤相关的Chk 2等位基因（13）不能结合或磷酸化Cdc 25 A，并且表达这些Chk 2等位基因的细胞，升高的Cdc 25 A或不能进行抑制性磷酸化的Cdk 2突变体（Cdk 2AF）在照射时不能抑制DNA合成。这些结果支持Chk 2作为候选肿瘤抑制因子，并将ATM-Chk 2-Cdc 25 A-Cdk 2途径鉴定为阻止抗辐射DNA合成的基因组完整性检查点。
When exposed to ionizing radiation (IR), eukaryotic cells activate checkpoint pathways to delay the progression of the cell cycle(1-3). Defects in the IR-induced S-phase checkpoint cause 'radioresistant DNA synthesis', a phenomenon that has been identified in cancer-prone patients suffering from ataxia-telangiectasia, a disease caused by mutations in the ATM gene(4-6). The Cdc25A phosphatase(7) activates the cyclin-dependent kinase 2 (Cdk2) needed for DNA synthesis(8,9), but becomes degraded in response to DNA damage(10) or stalled replication(11). Here we report a functional link between ATM, the checkpoint signalling kinase Chk2/Cds1 (Chk2)(12) and Cdc25A, and implicate this mechanism in controlling the S-phase checkpoint. We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123. An IR-induced loss of Cdc25A protein prevents dephosphorylation of Cdk2 and leads to a transient blockade of DNA replication. We also show that tumour-associated Chk2 alleles(13) cannot bind or phosphorylate Cdc25A, and that cells expressing these Chk2 alleles, elevated Cdc25A or a Cdk2 mutant unable to undergo inhibitory phosphorylation (Cdk2AF) fail to inhibit DNA synthesis when irradiated. These results support Chk2 as a candidate tumour suppressor, and identify the ATM-Chk2-Cdc25A-Cdk2 pathway as a genomic integrity checkpoint that prevents radioresistant DNA synthesis.