التفاصيل البيبلوغرافية
| العنوان: |
E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1. |
| المؤلفون: |
Da-Qiang Li1, Ohshiro, Kazufumi1, Reddy, Sirigiri Divijendra Natha1, Pakala, Suresh B.1, Mong-Hong Lee2, Yanping Zhang3, Rayala, Suresh K.1, Kumar, Rakesh1 bcmrxk@gwumc.edu |
| المصدر: |
Proceedings of the National Academy of Sciences of the United States of America. 10/13/2009, Vol. 106 Issue 41, p17493-17498. 6p. |
| مصطلحات موضوعية: |
*UBIQUITIN, *LIGASES, *GENETIC regulation, *METASTASIS, *PROTEOLYSIS, *IONIZING radiation, *DNA damage |
| مستخلص: |
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 autoubiquitination, 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. [ABSTRACT FROM AUTHOR] |
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