CSN6 deregulation impairs genome integrity in a COP1-dependent pathway

// Hyun Ho Choi 1, 2 , Chun-Hui Su 1 , Lekun Fang 1 , Jin Zhang 3 , Sai-Ching J. Yeung 4, 5 , Mong-Hong Lee 1, 2, 6, 7 1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 2 Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA 3 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 4 Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 5 Departiment of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 6 Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA 7 Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA Correspondence to: Mong-Hong Lee, e-mail: mhlee@mdanderson.org Keywords: p27, COP1, 14-3-3σ, ubiquitination, DNA damage Received: September 22, 2014      Accepted: January 17, 2015      Published: January 31, 2015 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.