المؤلفون: Da-Qiang Li¹, Pakala, Suresh B.¹, Reddy, Sirigiri Divijendra Natha¹, Ohshiro, Kazufumi¹, Shao-Hua Peng¹, Lian, Vi¹, Fu, Sidney W.¹, Kumar, Rakesh¹ bcmrxk@gwumc.edu

المصدر: Journal of Biological Chemistry. 3/26/2010, Vol. 285 Issue 13, p10044-10052. 9p.

مصطلحات موضوعية: *P53 antioncogene, *P53 protein, *TUMOR suppressor proteins, *CELL proliferation, *DNA damage, *CARCINOGENESIS, *LIGASES

مستخلص: Although metastasis-associated protein 1 (MTA1), a component of the nucleosome remodeling and deacetylase (NuRD) complex, is a DNA-damage response protein and regulates p53dependent DNA repair, it remains unknown whether MTA1 also participates in p53-independent DNA damage response. Here, we provide evidence that MTA1 is a p53-independent transcriptional corepressor of p21 WAF1, and the underlying mechanism involves recruitment of MTA1-histone deacetylase 2 (HDAC2) complexes onto two selective regions of the p21 WAF1 promoter. Accordingly, MTA1 depletion, despite its effect on p53 down-regulation, superinduces p21 WAF1, increases p21 WAF1 binding to proliferating cell nuclear antigen (PCNA), and decreases the nuclear accumulation of PCNA in response to ionizing radiation. In support of a p53-independent role of MTA1 in DNA damage response, we further demonstrate that induced expression of MTA1 in p53-null cells inhibits p21W promoter activity and p21WAF1 binding to PCNA. Consequently, MTA1 expression in p53-null cells results in increased induction of γH2AX foci and DNA double strand break repair, and decreased DNA damage sensitivity following ionizing radiation treatment. These findings uncover a new target of MTA1 and the existence of an additional p53-independent role of MTA1 in DNA damage response, at least in part, by modulating the p2WAF1-PCNA pathway, and thus, linking two previously unconnected NuRD complex and DNA-damage response pathways. [ABSTRACT FROM AUTHOR]

المؤلفون: Da-Qiang Li, Ohshiro, Kazufumi, Reddy, Sirigiri Divijendra Natha, Pakala, Suresh B., Mong-Hong Lee, Yanping Zhang, Rayala, Suresh K., Kumar, Rakesh

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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