E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 41; pp. 17493 - 17498
• Main Authors: Li, Da-Qiang, Ohshiro, Kazufumi, Reddy, Sirigiri Divijendra Natha, Pakala, Suresh B, Lee, Mong-Hong, Zhang, Yanping, Rayala, Suresh K, Kumar, Rakesh
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.10.2009; National Acad Sciences
• Subjects: Animals; Antibodies; Biological Sciences; Cancer; Cell Line; Cell lines; Chromatin; Deoxyribonucleic acid; DNA; DNA Damage; DNA Repair; Enzyme Stability; Fibroblasts - cytology; Fibroblasts - physiology; Gene expression regulation; Histone Deacetylases - chemistry; Histone Deacetylases - metabolism; Histone Deacetylases - radiation effects; histones; Humans; Ionizing radiation; Mice; mutants; Mutation; neoplasms; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; nucleosomes; photomorphogenesis; Physiological regulation; Plasmids; Proteases; Proteins; proteolysis; Radiation; Radiation, Ionizing; Regulator genes; Repressor Proteins - chemistry; Repressor Proteins - metabolism; Repressor Proteins - radiation effects; Trans-Activators; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - metabolism; Ubiquitin - metabolism; ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; ubiquitination; Ubiquitins
• DOI: 10.1073/pnas.0908027106
• ISSN: 0027-8424; 1091-6490

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.