E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1

被引:74
|
作者
Li, Da-Qiang [1 ,2 ]
Ohshiro, Kazufumi [1 ,2 ]
Reddy, Sirigiri Divijendra Natha [1 ,2 ]
Pakala, Suresh B. [1 ,2 ]
Lee, Mong-Hong [3 ]
Zhang, Yanping [4 ]
Rayala, Suresh K. [1 ,2 ]
Kumar, Rakesh [1 ,2 ,3 ]
机构
[1] George Washington Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20037 USA
[2] George Washington Univ, Med Ctr, Inst Coregulator Biol, Washington, DC 20037 USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA
[4] Univ N Carolina, Radiat Oncol & Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
基金
美国国家卫生研究院;
关键词
coregulator; DNA repair; ubiquitination; C-JUN; PROTEIN-1; PHOTOMORPHOGENESIS; REPRESSION; TRANSCRIPTION; GAMMA-H2AX; PROTEASOME; EXPRESSION; ACTIVATOR; INTERACTS;
D O I
10.1073/pnas.0908027106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Metastasis-associated protein 1 (MTA1), a component of the nucleosome remodeling and histone deacetylation (NuRD) complex, is widely upregulated in human cancers. However, the mechanism for regulating its protein stability remains unknown. Here we report that MTA1 is an ubiquitinated protein and targeted by the RING-finger E3 ubiquitin-protein ligase constitutive photomorphogenesis protein 1 (COP1) for degradation via the ubiquitin-proteasome pathway. Induced expression of wild-type COP1 but not its RING motif mutants promotes the ubiquitination and degradation of MTA1, indicating that the ligase activity is required for the COP1-mediated proteolysis of MTA1. Conversely, depletion of endogenous COP1 resulted in a marked decrease in MTA1 ubiquitination, accompanied by a pronounced accumulation of MTA1 protein. MTA1, in turn, destabilizes COP1 by promoting its auto-ubiquitination, thus creating a tight feedback loop that regulates both MTA1 and COP1 protein stability. Accordingly, disruption of the COP1-mediated proteolysis by ionizing radiation leads to MTA1 stabilization, accompanied by an increased coregulatory function of MTA1 on its target. Furthermore, we discovered that MTA1 is required for optimum DNA double-strand break repair after ionizing radiation. These findings provide novel insights into the regulation of MTA1 protein and reveal a novel function of MTA1 in DNA damage response.
引用
收藏
页码:17493 / 17498
页数:6
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