DNA-PKcs Negatively Regulates Cyclin B1 Protein Stability through Facilitating Its Ubiquitination Mediated by Cdh1-APC/C Pathway

Zeng-Fu Shang^1,2*, Wei Tan^2,3*, Xiao-Dan Liu^2*, Lan Yu⁴, Bing Li², Ming Li¹, Man Song^1,2, Yu Wang², Bei-Bei Xiao¹, Cai-Gao Zhong³, Hua Guan^2✉, Ping-Kun Zhou^1,2✉

1. School of Radiation Medicine and Protection, Medical College of Soochow University; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu 215123, P. R. China
2. Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology (BKLRB), Beijing Institute of Radiation Medicine, Beijing 100850, P. R. China
3. School of Public Heath, Central South University, Changsha, Hunan Province, Changsha, Hunan 410078, P. R. China
4. Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
^*These authors contributed equally to this work

Abstract

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.

Keywords: Cyclin B1, DNA-PKcs

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How to cite this article:
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-PKcs Negatively Regulates Cyclin B1 Protein Stability through Facilitating Its Ubiquitination Mediated by Cdh1-APC/C Pathway. Int J Biol Sci 2015; 11(9):1026-1035. doi:10.7150/ijbs.12443. Available from http://www.ijbs.com/v11p1026.htm