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      Pint lincRNA connects the p53 pathway with epigenetic silencing by the Polycomb repressive complex 2

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          Abstract

          Background

          The p53 transcription factor is located at the core of a complex wiring of signaling pathways that are critical for the preservation of cellular homeostasis. Only recently it has become clear that p53 regulates the expression of several long intergenic noncoding RNAs (lincRNAs). However, relatively little is known about the role that lincRNAs play in this pathway.

          Results

          Here we characterize a lincRNA named Pint (p53 induced noncoding transcript). We show that Pint is a ubiquitously expressed lincRNA that is finely regulated by p53. In mouse cells, Pint promotes cell proliferation and survival by regulating the expression of genes of the TGF-β, MAPK and p53 pathways. Pint is a nuclear lincRNA that directly interacts with the Polycomb repressive complex 2 (PRC2), and is required for PRC2 targeting of specific genes for H3K27 tri-methylation and repression. Furthermore, Pint functional activity is highly dependent on PRC2 expression. We have also identified Pint human ortholog ( PINT), which presents suggestive analogies with the murine lincRNA. PINT is similarly regulated by p53, and its expression significantly correlates with the same cellular pathways as the mouse ortholog, including the p53 pathway. Interestingly, PINT is downregulated in colon primary tumors, while its overexpression inhibits the proliferation of tumor cells, suggesting a possible role as tumor suppressor.

          Conclusions

          Our results reveal a p53 autoregulatory negative mechanism where a lincRNA connects p53 activation with epigenetic silencing by PRC2. Additionally, we show analogies and differences between the murine and human orthologs, identifying a novel tumor suppressor candidate lincRNA.

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          Most cited references18

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          Long noncoding RNA as modular scaffold of histone modification complexes.

          Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5' domain of HOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3' domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.
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            Requirement for p53 and p21 to sustain G2 arrest after DNA damage.

            After DNA damage, many cells appear to enter a sustained arrest in the G2 phase of the cell cycle. It is shown here that this arrest could be sustained only when p53 was present in the cell and capable of transcriptionally activating the cyclin-dependent kinase inhibitor p21. After disruption of either the p53 or the p21 gene, gamma radiated cells progressed into mitosis and exhibited a G2 DNA content only because of a failure of cytokinesis. Thus, p53 and p21 appear to be essential for maintaining the G2 checkpoint in human cells.
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              Polycomb silencers control cell fate, development and cancer.

              Polycomb group (PcG) proteins are epigenetic gene silencers that are implicated in neoplastic development. Their oncogenic function might be associated with their well-established role in the maintenance of embryonic and adult stem cells. In this review, we discuss new insights into the possible mechanisms by which PcGs regulate cellular identity, and speculate how these functions might be relevant during tumorigenesis.
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                Author and article information

                Contributors
                Journal
                Genome Biol
                Genome Biol
                Genome Biology
                BioMed Central
                1465-6906
                1465-6914
                2013
                26 September 2013
                : 14
                : 9
                : R104
                Affiliations
                [1 ]Center for Applied Medical Research, University of Navarra, 55 Pio XII Avenue., 31008 Pamplona, Spain
                [2 ]Department of Antisense Drug Discovery, Isis Pharmaceuticals, 2855 Gazelle Court., Carlsbad, CA 92008, USA
                [3 ]Department of Medical Oncology, Hospital Municipal de Badalona, 9-13 Via Augusta Street, 08911 Badalona, Spain
                [4 ]Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, University of Barcelona Medical School, IDIBAPS, 143 Casanova Street, 080360 Barcelona, Spain
                [5 ]Department of Oncology, Translational Oncology Division, Health Research Institute Fundación Jiménez Díaz University Hospital, Autonomous University of Madrid, 2 Reyes Catolicos Avenue, 28040 Madrid, Spain
                [6 ]Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA
                Article
                gb-2013-14-9-r104
                10.1186/gb-2013-14-9-r104
                4053822
                24070194
                eff868eb-bd97-4654-927b-b3e853de4cee
                Copyright © 2013 Marín-Béjar et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 April 2013
                : 11 July 2013
                : 26 September 2013
                Categories
                Research

                Genetics
                lincrna,non-coding rna,p53,gene regulation,polycomb repressive complex 2
                Genetics
                lincrna, non-coding rna, p53, gene regulation, polycomb repressive complex 2

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