Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
Cell Cycle. 2010 Nov 15;9(22):4592-9. doi: 10.4161/cc.9.22.13665.
We have previously shown that the DNA damage-induced G2 arrest is contributed by inhibition of Aurora A (AurA) and that transduction of active AurA into arrested cells allows bypassing the block through reactivation of CDK1. In this study, we investigated the mechanism of DNA damage-induced AurA inhibition. We provide evidence that ionizing radiation (IR) administered in mitosis, a time when AurA protein and enzymatic activity reach peak levels, impairs interaction with the partner TPX2, leading to inactivation of the kinase through dephosphorylation of AurA T-loop residue, T288. We find that decreased AurA-TPX2 complex formation in response to irradiation results from reduced cellular levels of TPX2, an effect that is both contributed by increased APC/CDH1-dependent protein degradation and decreased translation of TPX2 mRNA.
我们之前已经表明，DNA 损伤诱导的 G2 期阻滞是由 Aurora A（AurA）的抑制引起的，并且将活性 AurA 转导到被阻滞的细胞中可以通过重新激活 CDK1 来绕过该阻滞。在这项研究中，我们研究了 DNA 损伤诱导的 AurA 抑制的机制。我们提供的证据表明，在有丝分裂中给予电离辐射（IR），此时 AurA 蛋白和酶活性达到峰值水平，会损害与伴侣 TPX2 的相互作用，导致激酶失活，这是通过 AurA T 环残基 T288 的去磷酸化实现的。我们发现，由于细胞内 TPX2 水平降低，导致 AurA-TPX2 复合物形成减少，这种作用既是由 APC/CDH1 依赖性蛋白降解增加引起的，也是由 TPX2 mRNA 翻译减少引起的。
