Choi Hyun Ho, Su Chun-Hui, Fang Lekun, Zhang Jin, Yeung Sai-Ching J, Lee Mong-Hong
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA.
Oncotarget. 2015 May 20;6(14):11779-93. doi: 10.18632/oncotarget.3151.
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.
了解基因组完整性和DNA损伤反应对于癌症治疗至关重要。在本研究中，我们确定了CSN6在调节基因组完整性方面的生物学功能。组成型光形态建成1（COP1）是一种受CSN6调节的E3泛素连接酶，其在DNA损伤后会下调，但其生物学后果尚不清楚。p27（Kip1）是一种参与细胞周期调节的关键CDK抑制剂，但其对DNA损伤的反应仍不明确。在此，我们报道DNA损伤后p27（Kip1）水平升高，同时COP1水平降低。机制研究表明，在DNA损伤反应过程中，COP1作为p27的E3连接酶的功能受损，从而减少了泛素介导的p27（Kip1）降解。此外，COP1过表达导致p27（Kip1）下调，从而促进有丝分裂激酶Aurora A的表达。Aurora A的过表达与不良生存相关。这些发现为DNA损伤修复和肿瘤发生中的CSN6-COP1-p27（Kip1）-Aurora A轴提供了新的见解。
