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

TY - JOUR

T1 - Ribosomal protein mRNAs are primary targets of regulation in RNase-L-induced senescence

AU - Andersen, Jesper Bøje

AU - Mazan-Mamczarz, Krystyna

AU - Zhan, Ming

AU - Gorospe, Myriam

AU - Hassel, Bret A

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

KW - Animals

KW - Base Sequence

KW - Cell Aging

KW - Cell Line

KW - Down-Regulation

KW - Endoribonucleases

KW - Enzyme Activation

KW - Gene Expression Profiling

KW - Mice

KW - Mice, Knockout

KW - Nucleic Acid Conformation

KW - Protein Binding

KW - RNA, Messenger

KW - Ribosomal Proteins

M3 - Journal article

C2 - 19411840

SN - 1547-6286

VL - 6

SP - 305

EP - 315

JO - R N A Biology

JF - R N A Biology

IS - 3

ER -