التفاصيل البيبلوغرافية
| العنوان: |
Revelation of p53-independent Function of MTA1 in DNA Damage Response via Modulation of the p21 WAF1-proliferating Cell Nuclear Antigen Pathway. |
| 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] |
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