Ribosomal protein mRNAs are primary targets of regulation in RNase-L-induced senescence

Jesper B. Andersen, Krystyna Mazan-Mamczarz, Ming Zhan, Myriam Gorospe, Bret A. Hassel

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

The endoribonuclease RNase-L requires 2′,5′-linked oligoadenylates for activation, and mediates antiviral and antiproliferative activities. We previously determined that RNase-L activation induces senescence; to determine potential mechanisms underlying this activity, we used microarrays to identify RNase-L-regulated mRNAs. RNase-L activation affected affected a finite number of transcripts, and thus does not lead to a global change in mRNA turnover. The largest classes of downregulated transcripts, that represent candidate RNase-L substrates, function in protein biosynthesis, metabolism and proliferation. Among these, mRNAs encoding ribosomal proteins (RPs) were particularly enriched. The reduced levels of four RP mRNAs corresponded with a decrease in their half lives and a physical association with an RNase-L-ribonucleoprotein (RNP) complex in cells, suggesting that they represent authentic RNase-L substrates. Sequence and structural analysis of the down-regulated mRNAs identified a putative RNase-L target motif that was used for the in silico identification of a novel RNase-L-RNP-interacting transcript. The downregulation of RP mRNAs corresponded with a marked reduction in protein translation, consistent with the roles of RP proteins in ribosome function. Our data support a model in which the RNase-L-mediated degradation of RP mRNAs inhibits translation, and may contribute to its antiproliferative, senescence inducing and tumor suppressor activities.

Original languageEnglish (US)
Pages (from-to)305-315
Number of pages11
JournalRNA Biology
Volume6
Issue number3
DOIs
StatePublished - 2009

Keywords

  • 2′-5′- oligoadenylate
  • mRNA stability
  • Ribosomal protein
  • RNase-L
  • Senescence

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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