Oncotarget

Priority Research Papers:

CSN6 deregulation impairs genome integrity in a COP1-dependent pathway

Hyun Ho Choi _, Chun-Hui Su, Lekun Fang, Jin Zhang, Sai-Ching J. Yeung and Mong-Hong Lee

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Oncotarget. 2015; 6:11779-11793. https://doi.org/10.18632/oncotarget.3151

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Abstract

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

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. 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.


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