E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1.
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.
Li
Da-Qiang
DQ
Department of Biochemistry and Molecular Biology and Institute of Coregulator Biology, The George Washington University Medical Center, Washington, DC 20037, USA.
Ohshiro
Kazufumi
K
Reddy
Sirigiri Divijendra Natha
SD
Pakala
Suresh B
SB
Lee
Mong-Hong
MH
Zhang
Yanping
Y
Rayala
Suresh K
SK
Kumar
Rakesh
R
D000818:Animals; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004795:Enzyme Stability; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism* / Q000528:radiation effects; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism* / Q000528:radiation effects; D015534:Trans-Activators; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
C089320:MTA1 protein, human; C503336:Mta1 protein, mouse; D009687:Nuclear Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D025801:Ubiquitin; C471981:COP1 protein, human; C471982:COP1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D006655:Histone Deacetylases