文章：

ATM和相关蛋白激酶：保护基因组完整性

ATM and related protein kinases: safeguarding genome integrity

原文发布日期：2003-03-01

DOI: 10.1038/nrc1011

类型: Review Article

开放获取: 否

要点：

1. The DNA-damage response is crucial for cellular life and for avoiding neoplasia. It occurs by rapidly transducing the damage signal to many cellular systems, such as the DNA-repair machinery and the cell-cycle checkpoints.
2. Double-strand breaks (DSBs) in the DNA — deadly DNA lesions — mobilize an intricate signalling network by activating the ATM protein kinase, which, in turn, orchestrates this network by phosphorylating one or more key proteins in each of its branches.
3. Other protein kinases related to ATM carry out similar functions in response to other genotoxic stresses, and some of them collaborate with ATM in the DSB response.
4. ATM deficiency leads to ataxia-telangiectasia (A-T), a genomic instability syndrome, the hallmarks of which — neurodegeneration, immunodeficiency, radiation sensitivity and cancer predisposition — show the intimate connection between maintenance of genome stability, cellular and tissue functioning, and cancer prevention.
5. Certain types of ATM mutations seem to increase cancer predisposition in heterozygous carriers. This adds ATM to the list of genes that have sequence variations with important implications for public health, especially with regards to cancer epidemiology.

要点翻译：

1. DNA损伤应答对细胞生存及避免肿瘤发生至关重要。这一过程通过将损伤信号快速传导至多个细胞系统而实现，例如DNA修复机制和细胞周期检查点。
2. DNA双链断裂——这种致死性DNA损伤——通过激活ATM蛋白激酶来动员复杂的信号网络；随后，ATM激酶通过磷酸化其各分支通路中的一个或多个关键蛋白来协调这一网络。
3. 与ATM相关的其他蛋白激酶在应对其他基因毒性应激时发挥类似功能，其中部分激酶在DNA双链断裂应答中与ATM协同作用。
4. ATM缺陷会导致共济失调-毛细血管扩张症（A-T），这是一种基因组不稳定性综合征。其典型特征——神经退行性变、免疫缺陷、放射敏感性及癌症易感性——揭示了基因组稳定性维持、细胞与组织功能以及癌症预防之间的内在联系。
5. 特定类型的ATM突变似乎会增加杂合子携带者的癌症易感性。这使得ATM被列入对公共卫生（尤其在癌症流行病学方面）具有重要意义的基因序列变异清单。

英文摘要：

Maintenance of genome stability is essential for avoiding the passage to neoplasia. The DNA-damage response — a cornerstone of genome stability — occurs by a swift transduction of the DNA-damage signal to many cellular pathways. A prime example is the cellular response to DNA double-strand breaks, which activate the ATM protein kinase that, in turn, modulates numerous signalling pathways. ATM mutations lead to the cancer-predisposing genetic disorder ataxia-telangiectasia (A-T). Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers.

摘要翻译： 

维持基因组稳定性对于避免向肿瘤发展至关重要。DNA损伤反应——基因组稳定性的基石——通过将损伤信号迅速传递至多条细胞通路而实现。一个典型例子是细胞对DNA双链断裂的反应：ATM蛋白激酶被激活，进而调控众多信号通路。ATM突变会导致易患癌症的遗传性疾病——共济失调毛细血管扩张症（A-T）。深入理解ATM的作用机制，不仅为了解DNA损伤反应缺陷与癌症的关联提供了新视角，也使我们更接近解决部分A-T携带者癌症易感性的难题。

原文链接：

ATM and related protein kinases: safeguarding genome integrity