Revelation of p53-independent Function of MTA1 in DNA Damage Response via Modulation of the p21WAF1-Proliferating Cell Nuclear Antigen Pathway

Department of Biochemistry and Molecular Biology and Institute of Coregulator Biology, The George Washington University Medical Center, Washington, DC 20037, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2010; 285(13):10044-52. DOI: 10.1074/jbc.M109.079095
Source: PubMed


Although metastasis-associated protein 1 (MTA1), a component of the nucleosome remodeling and deacetylase (NuRD) complex, is a DNA-damage response protein and regulates p53-dependent 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 p21(WAF1) promoter activity and p21(WAF1) binding to PCNA. Consequently, MTA1 expression in p53-null cells results in increased induction of gamma H2AX 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 p21(WAF1)-PCNA pathway, and thus, linking two previously unconnected NuRD complex and DNA-damage response pathways.

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Available from: Sidney Wang Fu, May 26, 2015
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    • "A naturally occurring MTA1 variant, MTA1s, can sequester estrogen receptor-α in the cytoplasm (25). Estrogen receptor involvement is the first insight into the p53-independent function of MTA1 in the DNA damage response involving the p21/WAF1-proliferating cell nuclear antigen pathway (26). MTA1 is required for the ATR-mediated DNA damage checkpoint function (27). "
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    ABSTRACT: Overexpression of the metastasis-associated gene 1 (MTA1) has previously been found to be associated with progression of various cancer types to the metastasis stage. The function of MTA1 in laryngeal squamous cell carcinoma (LSCC) remains unclear. To explore the significance of MTA1 in the invasion and migration processes in LSCC, gene transfection and RNA interference (RNAi) were performed to study the biological function of MTA1 in the LSCC cell line, HEP-2. Results showed that MTA1 promoted the invasion, adhesion and migration behavior of LSCC cells. RNAi against MTA1 significantly decreased the malignant phenotypes of cancer cells. MTA1 may be important in the process of LSCC invasion and metastasis.
    Oncology letters 02/2014; 7(2):399-404. DOI:10.3892/ol.2013.1729 · 1.55 Impact Factor
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    • "Emerging data suggest that MTA1 had deacetylation activity on p53 and subsequently attenuated the transactivation function of p53 [19,20]. MTA1 was also identified as a p53-independent transcriptional corepressor of p21 (WAF1), which is a direct target of p53 and mediates p53-dependent G1 growth arrest [21]. "
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    ABSTRACT: The prognostic value of metastasis-associated gene 1 (MTA1) in nasopharyngeal carcinoma (NPC) has been suggested. However, there is still no direct evidence that MTA1 promotes NPC growth in vivo. In this study, we aimed to investigate the function of MTA1 in the regulation of NPC cell proliferation and tumorigenesis in vitro and in vivo. Stable MTA1 knockdown or overexpression NPC cell lines were employed. The effects of MTA1 depletion or overexpression on cell proliferation, colony formation, cell cycle progression were examined by MTT, colony formation and flow cytometry assay. The effects of MTA1 depletion on tumor growth in vivo were examined in mouse xenograft model. MTA1 knockdown or overexpression drastically changed the proliferation, colony formation and cell cycle of NPC cells in vitro. MTA1 depletion significantly suppressed NPC tumorigenesis in vivo. MTA1 promotes NPC cell proliferation via enhancing G1 to S phase transition, leading to increased tumor growth. Targeting MTA1 is a promising approach to reduce tumor burden of NPC.
    Journal of Experimental & Clinical Cancer Research 08/2013; 32(1):54. DOI:10.1186/1756-9966-32-54 · 4.43 Impact Factor
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    • "Microarray gene expression assays and data analysis has been performed as described previously [51]. In brief, rRNA reduction of the purified total RNA samples was performed using the RiboMinus™ Transcriptome Isolation Kit (Invitrogen, Carlsbad, CA). "
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    ABSTRACT: P21-activated kinase 1 (PAK1), a serine/threonine protein kinase, modulates many cellular processes by phosphorylating its downstream substrates. In addition to its role in the cytoplasm, PAK1 also affects gene transcription due to its nuclear localization and association with chromatin. It is now recognized that PAK1 kinase activity and its nuclear translocation are rapidly stimulated by ionizing radiation (IR), and that PAK1 activation is a component of the DNA damage response. Owing to the role of PAK1 in the cell survival, its association with the chromatin, and now, stimulation by ionizing radiation, we hypothesize that PAK1 may be contributing to modulation of genes with roles in cellular processes that might be important in the DNA damage response. The purpose of this study was to identify new PAK1 targets in response to ionizing radiation with putative role in the DNA damage response. We examined the effect of IR on the gene expression patterns in the murine embryonic fibroblasts with or without Pak1 using microarray technology. Differentially expressed transcripts were identified using Gene Spring GX 10.0.2. Pathway, network, functional analyses and gene family classification were carried out using Kyoto Encyclopedia of Genes and Genomes (KEGG), Ingenuity Pathway, Gene Ontology and PANTHER respectively. Selective targets of PAK1 were validated by RT-qPCR. For the first time, we provide a genome-wide analysis of PAK1 and identify its targets with potential roles in the DNA damage response. Gene Ontology analysis identified genes in the IR-stimulated cells that were involved in cell cycle arrest and cell death. Pathway analysis revealed p53 pathway being most influenced by IR responsive, PAK1 targets. Gene family of transcription factors was over represented and gene networks involved in DNA replication, repair and cellular signaling were identified. In brief, this study identifies novel PAK1 dependent IR responsive genes which reveal new aspects of PAK1 biology.
    PLoS ONE 08/2013; 8(8):e66585. DOI:10.1371/journal.pone.0066585 · 3.23 Impact Factor
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