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A p53-bound enhancer region controls a long intergenic noncoding RNA required for p53 stress response

Oncogene volume 35, pages 4399–4406 (2016)Cite this article

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Abstract

Genome-wide chromatin studies identified the tumor suppressor p53 as both a promoter and an enhancer-binding transcription factor. As an enhancer factor, p53 can induce local production of enhancer RNAs, as well as transcriptional activation of distal neighboring genes. Beyond the regulation of protein-coding genes, p53 has the capacity to regulate long intergenic noncoding RNA molecules (lincRNAs); however, their importance to the p53 tumor suppressive function remains poorly characterized. Here, we identified and characterized a novel p53-bound intronic enhancer that controls the expression of its host, the lincRNA00475 (linc-475). We demonstrate the requirement of linc-475 for the proper induction of a p53-dependent cell cycle inhibitory response. We further confirm the functional importance of linc-475 in the maintenance of CDKN1A/p21 levels, a cell cycle inhibitor and a major p53 target gene, following p53 activation. Interestingly, loss of linc-475 reduced the binding of both p53 and RNA polymerase II (RNAPII) to the promoter of p21, attenuating its transcription rate following p53 activation. Altogether, our data suggest a direct role of p53-bound enhancer domains in the activation of lincRNAs required for an efficient p53 transcriptional response.

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Author notes

  1. C A Melo and N Léveillé: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    C A Melo, N Léveillé, K Rooijers, A Tal & R Agami

  2. Hubrecht Institute-KNAW and University Medical Centre Utrecht, Utrecht, The Netherlands

    P J Wijchers, G Geeven & W de Laat

  3. Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Institute of Pathology and Molecular Immunology of the University of Porto (IPATIMUP), Porto, Portugal

    S A Melo

  4. Department of Genetics, Erasmus MC, Rotterdam University, Rotterdam, The Netherlands

    R Agami

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  1. C A Melo
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  2. N Léveillé
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  4. P J Wijchers
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Correspondence to N Léveillé or R Agami.

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Melo, C., Léveillé, N., Rooijers, K. et al. A p53-bound enhancer region controls a long intergenic noncoding RNA required for p53 stress response. Oncogene 35, 4399–4406 (2016). https://doi.org/10.1038/onc.2015.502

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