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.
Andersen
Jesper B
JB
Marlene and Stewart Greenebaum Cancer Center, University of Maryland Baltimore, School of Medicine, Baltimore, MD 21201, USA.
Mazan-Mamczarz
Krystyna
K
Zhan
Ming
M
Gorospe
Myriam
M
Hassel
Bret A
BA
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