Replication stress and chromatin context link ATM activation to a role in DNA replication.
Replication stress and chromatin context link ATM activation to a role in DNA replication.
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DOI：
10.1016/j.molcel.2013.10.019
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发表时间：
2013-12-12
期刊：
影响因子：
16
通讯作者：
Hammond, Ester M.
中科院分区：
文献类型：
--
作者：
Olcina, Monica M.;Foskolou, Iosifina P.;Anbalagan, Selvakumar;Senra, Joana M.;Pires, Isabel M.;Jiang, Yanyan;Ryan, Anderson J.;Hammond, Ester M.
ATM介导的反应DNA损伤的信号是肿瘤发生的障碍。在这里，我们询问复制压力是否也会对ATM信号起作用。我们证明，在没有DNA损伤的情况下，ATM在低氧诱导的异染色质样环境中对复制应激做出反应。在某些低氧条件下，复制应激发生在没有可检测到的DNA损伤的情况下。低氧还会诱导H3K9me3，这是一种与基因抑制和异染色质相关的组蛋白修饰。低氧诱导的复制应激和H3K9me3的增加导致ATM激活。重要的是，ATM可以防止DNA损伤在低氧中积累。最重要的是，我们描述了在H3K9me3增加的背景下，ATM在维持DNA复制率方面的应激特异性作用。此外，ATM介导的对癌基因诱导的复制应激的反应在低氧条件下被增强。综上所述，这些数据表明，低氧在DNA损伤反应的激活中起着关键作用，因此有助于形成这种肿瘤发生的屏障。在没有损伤的情况下，ATM在富含H3K9me3的环境中对复制应激做出反应ATM-S1981、H3K9me3和低氧的水平在体内相关性良好ATM在低氧中保持DNA复制率ATM防止DNA损伤在低氧条件下积累
ATM-mediated signaling in response to DNA damage is a barrier to tumorigenesis. Here we asked whether replication stress could also contribute to ATM signaling. We demonstrate that, in the absence of DNA damage, ATM responds to replication stress in a hypoxia-induced heterochromatin-like context. In certain hypoxic conditions, replication stress occurs in the absence of detectable DNA damage. Hypoxia also induces H3K9me3, a histone modification associated with gene repression and heterochromatin. Hypoxia-induced replication stress together with increased H3K9me3 leads to ATM activation. Importantly, ATM prevents the accumulation of DNA damage in hypoxia. Most significantly, we describe a stress-specific role for ATM in maintaining DNA replication rates in a background of increased H3K9me3. Furthermore, the ATM-mediated response to oncogene-induced replication stress is enhanced in hypoxic conditions. Together, these data indicate that hypoxia plays a critical role in the activation of the DNA damage response, therefore contributing to this barrier to tumorigenesis. In the absence of damage, ATM responds to replication stress in H3K9me3-rich contexts The levels of ATM-S1981, H3K9me3, and hypoxia correlate well in vivo ATM maintains DNA replication rates in hypoxia ATM prevents the accumulation of DNA damage in hypoxic conditions
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