Li Da-Qiang, Ohshiro Kazufumi, Reddy Sirigiri Divijendra Natha, Pakala Suresh B, Lee Mong-Hong, Zhang Yanping, Rayala Suresh K, Kumar Rakesh
Department of Biochemistry and Molecular Biology and Institute of Coregulator Biology, The George Washington University Medical Center, Washington, DC 20037, USA.
Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17493-8. doi: 10.1073/pnas.0908027106. Epub 2009 Sep 24.
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.
转移相关蛋白1（MTA1）是核小体重塑和组蛋白去乙酰化（NuRD）复合物的一个组成部分，在人类癌症中广泛上调。然而，调节其蛋白质稳定性的机制仍不清楚。在此我们报告，MTA1是一种泛素化蛋白，被环指E3泛素蛋白连接酶组成型光形态建成蛋白1（COP1）靶向，通过泛素-蛋白酶体途径进行降解。野生型COP1而非其环基序突变体的诱导表达促进了MTA1的泛素化和降解，表明连接酶活性是COP1介导的MTA1蛋白水解所必需的。相反，内源性COP1的缺失导致MTA1泛素化显著降低，同时MTA1蛋白明显积累。反过来，MTA1通过促进COP1的自身泛素化使其不稳定，从而形成一个紧密的反馈环，调节MTA1和COP1的蛋白质稳定性。因此，电离辐射破坏COP1介导的蛋白水解会导致MTA1稳定，同时MTA1对其靶标的共调节功能增强。此外，我们发现电离辐射后最佳的DNA双链断裂修复需要MTA1。这些发现为MTA1蛋白的调节提供了新的见解，并揭示了MTA1在DNA损伤反应中的新功能。
