Resumen de Post-transcriptional regulation by unr: Insights into histone mrna metabolism and cellular senescence
RNA-binding proteins guide post-transcriptional control of gene expression and are emerging as important regulators in disease. UNR (CSDE1) is a conserved RNA-binding protein that regulates mRNA stability and translation. In melanoma, UNR promotes metastasis and binds to around 1500 transcripts which encode, among other proteins, pro-metastatic regulators, histones and SASP (senescence associated secretory phenotype) factors. Here we study two separate aspects of UNR: its potential role in regulation of histone transcripts and its role in senescence.
UNR binds to mature histone transcripts upstream of the 3’ UTR stem-loop, the main regulatory cis element of these mRNAs. RNA-Seq experiments revealed that histone mRNA levels are reduced upon UNR depletion. As UNR is mostly cytoplasmic we hypothesized that UNR might be regulating stabilization and/or translation in this cell compartment. Several approaches were undertaken to elucidate the molecular function of UNR in this context. However, we could not detect any specific role of UNR on histone mRNAs. If any, a non-specific effect of UNR in transcription was detected.
SASP factors are activated upon senescence induction. Using primary mouse keratinocytes (PMK) we explored the role of UNR in oncogene-induced senescence (OIS) and unveiled novel tumour suppressive properties of UNR. Depletion of UNR leads to senescence bypass, proliferation and immortalization. In addition, UNR contributes to modulation of the microenvironment through the SASP. RNA-seq analysis indicates that senescence bypass occurs concomitant with activation of cancer-related pathways, and without significant changes in the levels of cell cycle inhibitors. Our data suggest that UNR is an important regulator of the post-transcriptional senescent program. Further studies are necessary to elucidate the crucial UNR targets and/or partners in OIS.
