Single- and double-stranded DNA: building a trigger of ATR-mediated DNA damage response
Single- and double-stranded DNA: building a trigger of ATR-mediated DNA damage response
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DOI：
10.1101/gad.1550307
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发表时间：
2007-04-15
影响因子：
10.5
通讯作者：
Zou, Lee
中科院分区：
文献类型：
--
作者：
Zou, Lee
由共济失调-毛细血管扩张突变（ATM）和ATM和Rad 3相关（ATR）激酶介导的DNA损伤信号通路在维持基因组完整性方面起着至关重要的作用，并可能在早期肿瘤发生期间起着抗癌屏障的作用。虽然ATM和ATR途径共享它们的一些下游功能，但引起这两种途径的DNA损伤是不同的。虽然ATM在对双链DNA断裂（DSB）的反应中起主要作用，但ATR控制着对更广泛的DNA损伤的反应，包括许多干扰DNA复制的反应。而且，与ATM不同，ATR对于在细胞周期的S期维持基因组完整性至关重要，并且对于细胞存活不可或缺。显然，揭示启动ATR途径的DNA结构将是理解ATR的基本功能及其对抗的基因组不稳定性的关键一步。ATR途径在DNA损伤反应中的多功能性表明，该途径可能能够感知由不同类型的DNA损伤和基因组不稳定性产生的共同信号。在DNA修复和应激DNA复制叉位点通常产生的两种简单结构是被复制蛋白A包被的单链DNA（RPA-ssDNA）和单链和双链DNA的连接。通过使用不同模式生物的许多研究，这两种结构都与ATR检查点的激活有关。在这一期的《基因与发育》杂志中，Cimprich及其同事（MacDougall et al. 2007）报告说，用引物退火的环状单链DNA（ssDNA）特异性地触发了非洲爪蟾卵提取物中ATR介导的检查点反应，揭示了足以激活ATR检查点途径的第一个确定的DNA结构。
The DNA damage signaling pathways mediated by the ataxia-telangiectasia mutated (ATM) and the ATM and Rad3-related (ATR) kinases play crucial roles in the maintenance of genomic integrity and may function as an anti-cancer barrier during early tumorigenesis. Although the ATM and ATR pathways share some of their downstream functions, the DNA damage that evoke these two pathways are distinct. While ATM plays a primary role in the response to double-stranded DNA breaks (DSBs), ATR controls the response to a much broader spectrum of DNA damage, including many that interfere with DNA replication. And, unlike ATM, ATR is crucial for maintaining genomic integrity during S phase of the cell cycle, and is indispensable for cell survival. Clearly, revealing the DNA structure that elicits the ATR pathway would be a critical step toward understanding the essential function of ATR and the genomic instability that it counters. The versatility of the ATR pathway in DNA damage response suggests that this pathway is likely able to sense a common signal generated by different types of DNA damage and genomic instability. Two simple structures commonly generated at sites of DNA repair and stressed DNA replication forks are single-stranded DNA coated with replication protein A (RPA-ssDNA) and junctions of single-and doublestranded DNA. Both of these structures have been implicated in the activation of ATR checkpoint by a number of studies using different model organisms. In this issue of Genes & Development, Cimprich and colleagues (MacDougall et al. 2007) report that circular singlestranded DNA (ssDNA) annealed with primers specifically triggers the ATR-mediated checkpoint responses in Xenopus egg extracts, revealing the first defined DNA structure sufficient to activate the ATR checkpoint pathway.