title: DNA-PKcs Negatively Regulates Cyclin B1 Protein Stability through Facilitating Its Ubiquitination Mediated by Cdh1-APC/C Pathway.
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.
authors.affiliation: 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.
authors.forename: Zeng-Fu
authors.initials: ZF
authors.lastname: Shang
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.affiliation: 2. Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology (BKLRB), Beijing Institute of Radiation Medicine, Beijing 100850, P. R. China.
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Liu
authors.affiliation: 4. Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Yu
authors.affiliation: 2. Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology (BKLRB), Beijing Institute of Radiation Medicine, Beijing 100850, P. R. China.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Man
authors.initials: M
authors.lastname: Song
authors.affiliation: 2. Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology (BKLRB), Beijing Institute of Radiation Medicine, Beijing 100850, P. R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Xiao
authors.affiliation: 3. School of Public Heath, Central South University, Changsha, Hunan Province, Changsha, Hunan 410078, P. R. China.
authors.forename: Cai-Gao
authors.initials: CG
authors.lastname: Zhong
authors.affiliation: 2. Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology (BKLRB), Beijing Institute of Radiation Medicine, Beijing 100850, P. R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Guan
authors.affiliation: 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.
authors.forename: Ping-Kun
authors.initials: PK
authors.lastname: Zhou
mesh_terms: D064200:Cdh1 Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism*; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D055550:Protein Stability; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D054875:Ubiquitination / Q000235:genetics / Q000502:physiology
chemical_list: D064200:Cdh1 Proteins; D056744:Cyclin B1; D051747:DNA-Activated Protein Kinase
keywords: Cyclin B1; DNA-PKcs