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.
Highlights
The COP9 signalosome (CSN) is a protein complex involved in protein degradation, transcriptional activation [1, 2], signal transduction [3,4,5,6], and tumorigenesis [5, 7,8,9,10]
Constitutive photomorphogenic 1 (COP1), an E3 ubiquitin ligase regulated by COP9 signalosome subunit 6 (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
We found that these CSN6 expressing clones have elevated reactive oxygen species (ROS), suggesting potential DNA damage (Figure 1B)
Summary
The COP9 signalosome (CSN) is a protein complex involved in protein degradation, transcriptional activation [1, 2], signal transduction [3,4,5,6], and tumorigenesis [5, 7,8,9,10]. The contribution of the CSN’s subunits in cancer has not been well elucidated. Mammalian CSN subunits are involved in developmental processes: targeted disruptions of mammalian Csn, Csn, Csn, and Csn resulted in defective embryo development [11,12,13,14]. We performed targeted disruption of the Csn gene in mice and found that Csn6-/- mice developed until 7.5 days post-coitus but not beyond this time [9]. The mechanism and biological consequence of CSN6 overexpression in cancer remain unclear
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