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bioRxiv · 10.1101/2024.10.09.617433

Sm-site containing mRNAs can accept Sm-rings and are downregulated in Spinal Muscular Atrophy

Blatnik, A. J.·Sanjeev, M.·Slivka, J. A.·Pastore, B.·Embree, C. M.·Tang, W.·Singh, G.·Burghes, A. H. M.
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Abstract

Sm-ring assembly is important for the biogenesis, stability, and function of uridine-rich small nuclear RNAs (U snRNAs) involved in pre-mRNA splicing and histone pre-mRNA processing. Sm-ring assembly is cytoplasmic and dependent upon the Sm-site sequence and structural motif, ATP, and Survival motor neuron (SMN) protein complex. While RNAs other than U snRNAs were previously shown to associate with Sm proteins, whether this association follows Sm-ring assembly requirements is unknown. We systematically identified Sm-sites within the human and mouse transcriptomes and assessed whether these sites can accept Sm-rings. In addition to snRNAs, Sm-sites are highly prevalent in the 3 untranslated regions of long messenger RNAs. RNA immunoprecipitation experiments confirm that Sm-site containing mRNAs associate with Sm proteins in the cytoplasm. In modified Sm-ring assembly assays, Sm-site containing RNAs, from either bulk polyadenylated RNAs or those transcribed in vitro, specifically associate with Sm proteins in an Sm-site and ATP-dependent manner. In cell and animal models of Spinal Muscular Atrophy (SMA), mRNAs containing Sm-sites are downregulated, suggesting reduced Sm-ring assembly on these mRNAs may contribute to SMA pathogenesis. Together, this study establishes that Sm-site containing mRNAs can accept Sm-rings and identifies a novel mechanism for Sm proteins in regulation of cytoplasmic mRNAs. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/617433v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@d50f03org.highwire.dtl.DTLVardef@1cca1dforg.highwire.dtl.DTLVardef@1976fcaorg.highwire.dtl.DTLVardef@12c41d9_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Blatnik, A. J., Sanjeev, M., Slivka, J. A., Pastore, B., Embree, C. M., Tang, W., Singh, G., Burghes, A. H. M.. 2024-10-09. Sm-site containing mRNAs can accept Sm-rings and are downregulated in Spinal Muscular Atrophy. https://doi.org/10.1101/2024.10.09.617433

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