CSN6 deregulation impairs genome integrity in a COP1-dependent pathway

被引：14

作者：

Choi, Hyun Ho ^{[1
,2
]}

Su, Chun-Hui ^{[1
]}

Fang, Lekun ^{[1
]}

Zhang, Jin ^{[3
]}

Yeung, Sai-Ching J. ^{[4
,5
]}

Lee, Mong-Hong ^{[1
,2
,6
,7
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[2] Texas A&M Univ, Hlth Sci Ctr, Inst Biosci & Technol, Houston, TX 77030 USA

[3] Tianjin Med Univ, Key Lab Breast Canc Prevent & Therapy, Minist Educ, Canc Inst & Hosp,Natl Clin Res Ctr Canc, Tianjin, Peoples R China

[4] Univ Texas MD Anderson Canc Ctr, Dept Emergency Med, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA

[6] Univ Texas Houston, Grad Sch Biomed Sci, Program Canc Biol, Houston, TX 77030 USA

[7] Univ Texas Houston, Grad Sch Biomed Sci, Program Genes & Dev, Houston, TX 77030 USA

来源：

ONCOTARGET | 2015年 / 6卷 / 14期

基金：

美国国家卫生研究院;

关键词：

p27; COP1; 14-3-3; sigma; ubiquitination; DNA damage; DEPENDENT-KINASE INHIBITOR; UBIQUITIN LIGASE COP1; CELL-CYCLE; C/EBP-ALPHA; DEGRADATION; 14-3-3-SIGMA; P27(KIP1); PHOTOMORPHOGENESIS; P53; PHOSPHORYLATES;

D O I：

10.18632/oncotarget.3151

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：11779 / 11793

页数：15

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