DNA-PKcs Negatively Regulates Cyclin B1 Protein Stability through Facilitating Its Ubiquitination Mediated by Cdh1-APC/C Pathway.
DNA-PKcs Negatively Regulates Cyclin B1 Protein Stability through Facilitating Its Ubiquitination Mediated by Cdh1-APC/C Pathway.
复制标题
DNA-PKcs 通过促进 Cdh1-APC/C 通路介导的泛素化来负向调节 Cyclin B1 蛋白的稳定性。
DOI：
10.7150/ijbs.12443
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发表时间：
2015
影响因子：
9.2
通讯作者：
Zhou PK
中科院分区：
文献类型：
--
作者：
Shang ZF;Tan W;Liu XD;Yu L;Li B;Li M;Song M;Wang Y;Xiao BB;Zhong CG;Guan H;Zhou PK
DNA依赖性蛋白激酶（DNA- pkcs）的催化亚基是DNA双链断裂修复非同源末端连接途径的关键组成部分。DNA-PKcs最近也被证明在有丝分裂调节中起作用。本文报道DNA-PKcs通过Cdh1 / e3泛素连接酶APC/C途径促进Cyclin B1蛋白泛素化，从而负向调控Cyclin B1蛋白的稳定性。DNA-PKcs的缺失导致细胞周期蛋白B1的异常积累。在dna - pkcs缺陷细胞中，由于泛素化的减弱，细胞周期蛋白B1的降解被延迟。DNA-PKcs对Cyclin B1稳定性的影响依赖于其激酶活性。我们的研究进一步揭示了DNA-PKcs与APC/C核心组分APC2及其共激活子Cdh1相互作用。在没有DNA-PKcs的情况下，Cdh1的破坏会加速。此外，外源性Cdh1的过表达可以逆转dna - pkcs缺陷细胞中Cyclin B1蛋白的升高。因此，DNA- pkcs除了在DNA损伤修复中的直接作用外，还至少部分通过调节Cyclin B1蛋白的稳定性在有丝分裂过程中发挥作用。
The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is a critical component of the non-homologous end-joining pathway of DNA double-stranded break repair. DNA-PKcs has also been shown recently functioning in mitotic regulation. Here, we report that DNA-PKcs negatively regulates the stability of Cyclin B1 protein through facilitating its ubiquitination mediated by Cdh1 / E 3 ubiquitin ligase APC/C pathway. Loss of DNA-PKcs causes abnormal accumulation of Cyclin B1 protein. Cyclin B1 degradation is delayed in DNA-PKcs-deficient cells as result of attenuated ubiquitination. The impact of DNA-PKcs on Cyclin B1 stability relies on its kinase activity. Our study further reveals that DNA-PKcs interacts with APC/C core component APC2 and its co-activator Cdh1. The destruction of Cdh1 is accelerated in the absence of DNA-PKcs. Moreover, overexpression of exogenous Cdh1 can reverse the increase of Cyclin B1 protein in DNA-PKcs-deficient cells. Thus, DNA-PKcs, in addition to its direct role in DNA damage repair, functions in mitotic progression at least partially through regulating the stability of Cyclin B1 protein.