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Selective inhibition of microRNA accessibility by RBM38 is required for p53 activity

Author

Listed:
  • Nicolas Léveillé

    (The Netherlands Cancer Institute, Plesmanlaan 121)

  • Ran Elkon

    (The Netherlands Cancer Institute, Plesmanlaan 121)

  • Veronica Davalos

    (Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Via de L'Hospitalet 199-203, 08908 L'Hospitalet de Llobregat, Barcelona)

  • Vijayalaxmi Manoharan

    (MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.)

  • Dave Hollingworth

    (MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.)

  • Joachim Oude Vrielink

    (The Netherlands Cancer Institute, Plesmanlaan 121)

  • Carlos le Sage

    (The Netherlands Cancer Institute, Plesmanlaan 121)

  • Carlos A. Melo

    (The Netherlands Cancer Institute, Plesmanlaan 121
    Doctoral Program in Biomedicine and Experimental Biology, Center for Neuroscience and Cell Biology, University of Coimbra)

  • Hugo M. Horlings

    (Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.)

  • Jelle Wesseling

    (The Netherlands Cancer Institute)

  • Jernej Ule

    (Medical Research Council Laboratory of Molecular Biology)

  • Manel Esteller

    (Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Via de L'Hospitalet 199-203, 08908 L'Hospitalet de Llobregat, Barcelona)

  • Andres Ramos

    (MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.)

  • Reuven Agami

    (The Netherlands Cancer Institute, Plesmanlaan 121
    Centre for Biomedical Genetics, Universiteitsweg 100)

Abstract

MicroRNAs (miRNAs) interact with 3′-untranslated regions of messenger RNAs to restrict expression of most protein-coding genes during normal development and cancer. RNA-binding proteins (RBPs) can control the biogenesis, stability and activity of miRNAs. Here we identify RBM38 in a genetic screen for RBPs whose expression controls miRNA access to target mRNAs. RBM38 is induced by p53 and its ability to modulate miRNA-mediated repression is required for proper p53 function. In contrast, RBM38 shows lower propensity to block the action of the p53-controlled miR-34a on SIRT1. Target selectivity is determined by the interaction of RBM38 with uridine-rich regions near miRNA target sequences. Furthermore, in large cohorts of human breast cancer, reduced RBM38 expression by promoter hypermethylation correlates with wild-type p53 status. Thus, our results indicate a novel layer of p53 gene regulation, which is required for its tumour suppressive function.

Suggested Citation

  • Nicolas Léveillé & Ran Elkon & Veronica Davalos & Vijayalaxmi Manoharan & Dave Hollingworth & Joachim Oude Vrielink & Carlos le Sage & Carlos A. Melo & Hugo M. Horlings & Jelle Wesseling & Jernej Ule , 2011. "Selective inhibition of microRNA accessibility by RBM38 is required for p53 activity," Nature Communications, Nature, vol. 2(1), pages 1-11, September.
    • Handle: RePEc:nat:natcom:v:2:y:2011:i:1:d:10.1038_ncomms1519
    DOI: 10.1038/ncomms1519
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