title: CSN6 deregulation impairs genome integrity in a COP1-dependent pathway.
abstract: Understanding genome integrity and DNA damage response are critical to cancer treatment. In this study, we identify CSN6's biological function in regulating genome integrity. Constitutive photomorphogenic 1 (COP1), an E3 ubiquitin ligase regulated by CSN6, is downregulated by DNA damage, but the biological consequences of this phenomenon are poorly understood. p27(Kip1) is a critical CDK inhibitor involved in cell cycle regulation, but its response to DNA damage remains unclear. Here, we report that p27(Kip1) levels are elevated after DNA damage, with concurrent reduction of COP1 levels. Mechanistic studies showed that during DNA damage response COP1's function as an E3 ligase of p27 is compromised, thereby reducing the ubiquitin-mediated degradation of p27(Kip1). Also, COP1 overexpression leads to downregulation of p27(Kip1), thereby promoting the expression of mitotic kinase Aurora A. Overexpression of Aurora A correlates with poor survival. These findings provide new insight into CSN6-COP1-p27(Kip1)-Aurora A axis in DNA damage repair and tumorigenesis.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA.
authors.forename: Hyun Ho
authors.initials: HH
authors.lastname: Choi
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Su
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lekun
authors.initials: L
authors.lastname: Fang
authors.affiliation: Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Departiment of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sai-Ching J
authors.initials: SC
authors.lastname: Yeung
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA.|Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.|Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: Mong-Hong
authors.initials: MH
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000075686:COP9 Signalosome Complex; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000235:genetics*; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C470634:COPS6 protein, human; C471981:COP1 protein, human; D044767:Ubiquitin-Protein Ligases; D000075686:COP9 Signalosome Complex
keywords: 14-3-3σ; COP1; DNA damage; p27; ubiquitination