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

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, Manel Esteller, Andres Ramos, Reuven Agami

Research output: Contribution to journalArticlepeer-review

Abstract

MicroRNAs (miRNAs) interact with 3ĝ€2-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.

Original languageEnglish
Article number513
JournalNature Communications
Volume2
Issue number1
DOIs
StatePublished - 2011
Externally publishedYes

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