Ribosomal protein mRNAs are primary targets of regulation in RNase-L-induced senescence.
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 downregulated 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.
Marlene and Stewart Greenebaum Cancer Center, University of Maryland Baltimore, School of Medicine, Baltimore, MD 21201, USA.
Jesper B
JB
Andersen
Krystyna
K
Mazan-Mamczarz
Ming
M
Zhan
Myriam
M
Gorospe
Bret A
BA
Hassel
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D016922:Cellular Senescence; D015536:Down-Regulation; D004722:Endoribonucleases / Q000172:deficiency / Q000378:metabolism*; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D051379:Mice; D018345:Mice, Knockout; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D012269:Ribosomal Proteins; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease