Department of Radiation Oncology, The Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Mol Cell. 2011 Nov 18;44(4):597-608. doi: 10.1016/j.molcel.2011.09.016.
The ATM kinase plays a critical role in the maintenance of genetic stability. ATM is activated in response to DNA damage and is essential for cell-cycle checkpoints. Here, we report that ATM is activated in mitosis in the absence of DNA damage. We demonstrate that mitotic ATM activation is dependent on the Aurora-B kinase and that Aurora-B phosphorylates ATM on serine 1403. This phosphorylation event is required for mitotic ATM activation. Further, we show that loss of ATM function results in shortened mitotic timing and a defective spindle checkpoint, and that abrogation of ATM Ser1403 phosphorylation leads to this spindle checkpoint defect. We also demonstrate that mitotically activated ATM phosphorylates Bub1, a critical kinetochore protein, on Ser314. ATM-mediated Bub1 Ser314 phosphorylation is required for Bub1 activity and is essential for the activation of the spindle checkpoint. Collectively, our data highlight mechanisms of a critical function of ATM in mitosis.
ATM 激酶在维持遗传稳定性方面起着关键作用。ATM 会对 DNA 损伤做出反应，对于细胞周期检查点至关重要。在这里，我们报告说，即使在没有 DNA 损伤的情况下，ATM 在有丝分裂中也会被激活。我们证明，有丝分裂中 ATM 的激活依赖于 Aurora-B 激酶，并且 Aurora-B 会在丝氨酸 1403 上对 ATM 进行磷酸化。该磷酸化事件是有丝分裂中 ATM 激活所必需的。此外，我们还表明，ATM 功能丧失会导致有丝分裂时间缩短和纺锤体检查点缺陷，而 ATM Ser1403 磷酸化的缺失会导致该纺锤体检查点缺陷。我们还证明，有丝分裂中激活的 ATM 会在丝氨酸 314 上对 Bub1（一个关键的着丝粒蛋白）进行磷酸化。ATM 介导的 Bub1 Ser314 磷酸化对于 Bub1 活性是必需的，并且对于纺锤体检查点的激活也是必需的。总的来说，我们的数据强调了 ATM 在有丝分裂中发挥关键作用的机制。
