Priority Research Papers:
CSN6 deregulation impairs genome integrity in a COP1-dependent pathway
Metrics: PDF 2408 views | HTML 2354 views | ?
Hyun Ho Choi1,2, Chun-Hui Su1, Lekun Fang1, Jin Zhang3, Sai-Ching J. Yeung4,5, Mong-Hong Lee1,2,6,7
1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA
3Key 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
4Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
5Departiment of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
6Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
7Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
Mong-Hong Lee, e-mail: email@example.com
Keywords: p27, COP1, 14-3-3σ, ubiquitination, DNA damage
Received: September 22, 2014 Accepted: January 17, 2015 Published: January 31, 2015
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. p27Kip1 is a critical CDK inhibitor involved in cell cycle regulation, but its response to DNA damage remains unclear. Here, we report that p27Kip1 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 p27Kip1. Also, COP1 overexpression leads to downregulation of p27Kip1, 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-p27Kip1-Aurora A axis in DNA damage repair and tumorigenesis.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.