ATM regulates Cdt1 stability during the unperturbed S phase to prevent re-replication.
ATM regulates Cdt1 stability during the unperturbed S phase to prevent re-replication.
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DOI：
10.4161/cc.27274
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Fujita M
中科院分区：
文献类型：
--
作者：
Iwahori S;Kohmon D;Kobayashi J;Tani Y;Yugawa T;Komatsu K;Kiyono T;Sugimoto N;Fujita M
共济失调-毛细血管扩张突变(ATM)在DNA损伤反应中发挥重要作用，特别是在DNA双链断裂(DSB)方面。然而，ATM似乎不仅可以被DSB激活，还可以被染色质结构的一些变化激活，这表明ATM在细胞周期控制中具有潜在的功能。在这里，我们发现ATM在无动于衷的S阶段参与了CDT1的及时降解，CDT1是一个关键的复制许可因子。至少在某些类型的细胞中，p27Kip1的降解也受到ATM抑制的影响。新的ATM对CDT1的调节功能依赖于它的激酶活性和NBS1。事实上，我们发现在S阶段，ATM在Ser1981被适度磷酸化。ATM沉默诱导了Skp2水平的部分降低，Skp2是SCFSkp2泛素连接酶的一个组成部分，控制CDT1的降解。此外，Skp2沉默导致CDT1稳定，就像ATM抑制一样。此外，正如以前报道的那样，ATM沉默部分阻止了Akt在Ser473处的磷酸化，这表明它被激活，而Akt的抑制导致了CDT1的适度稳定。因此，ATM-Akt-SCFSkp2通路可能部分参与了这一新的ATM功能。最后，ATM抑制使细胞对再复制的诱导高度敏感，这表明了维持基因组稳定性的重要性。
Ataxia-telangiectasia mutated (ATM) plays crucial roles in DNA damage responses, especially with regard to DNA double-strand breaks (DSBs). However, it appears that ATM can be activated not only by DSB, but also by some changes in chromatin architecture, suggesting potential ATM function in cell cycle control. Here, we found that ATM is involved in timely degradation of Cdt1, a critical replication licensing factor, during the unperturbed S phase. At least in certain cell types, degradation of p27Kip1 was also impaired by ATM inhibition. The novel ATM function for Cdt1 regulation was dependent on its kinase activity and NBS1. Indeed, we found that ATM is moderately phosphorylated at Ser1981 during the S phase. ATM silencing induced partial reduction in levels of Skp2, a component of SCFSkp2 ubiquitin ligase that controls Cdt1 degradation. Furthermore, Skp2 silencing resulted in Cdt1 stabilization like ATM inhibition. In addition, as reported previously, ATM silencing partially prevented Akt phosphorylation at Ser473, indicative of its activation, and Akt inhibition led to modest stabilization of Cdt1. Therefore, the ATM-Akt-SCFSkp2 pathway may partly contribute to the novel ATM function. Finally, ATM inhibition rendered cells hypersensitive to induction of re-replication, indicating importance for maintenance of genome stability.
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DOI：
10.4161/cc.9.5.10914
发表时间：
2010-03-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Bashir T;Pagan JK;Busino L;Pagano M
通讯作者：
Pagano M
影响因子：
64.8
作者：
Bashir, T;Dorrello, NV;Pagano, M
通讯作者：
Pagano, M
影响因子：
2.3
作者：
Fujita M
通讯作者：
Fujita M
影响因子：
11.4
作者：
Barre, Benjamin;Perkins, Neil D.
通讯作者：
Perkins, Neil D.
影响因子：
4.4
作者：
Ito, Keisuke;Takubo, Keiyo;Hirao, Atsushi
通讯作者：
Hirao, Atsushi