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

Area of Science:

• Molecular Biology
• RNA Biology
• Gene Regulation

Background:

• Sm-ring assembly is essential for uridine-rich small nuclear RNA (U snRNA) biogenesis, stability, and function in pre-messenger RNA (mRNA) splicing.
• Sm-ring assembly occurs in the cytoplasm and requires specific Sm-site sequences, ATP, and the Survival Motor Neuron (SMN) protein complex.

Purpose of the Study:

• To investigate whether RNAs other than U snRNAs can associate with Sm proteins following Sm-ring assembly requirements.
• To identify and characterize Sm-sites in the human and mouse transcriptomes and determine their capacity to bind Sm-rings.

Main Methods:

• Systematic identification of Sm-sites in human and mouse transcriptomes.
• RNA immunoprecipitation experiments to confirm Sm protein association with Sm-site-containing mRNAs.
• Modified Sm-ring assembly assays to assess Sm-protein binding dependency on Sm-sites, SMN, and ATP.

Main Results:

• Sm-sites are highly prevalent in the 3' untranslated regions of long mRNAs, in addition to snRNAs.
• Sm-site-containing mRNAs associate with Sm proteins in the cytoplasm in an Sm-site, SMN, and ATP-dependent manner.
• Downregulation of Sm-site-containing mRNAs in cell and animal models of Spinal Muscular Atrophy (SMA) was observed.

Conclusions:

• This study establishes that Sm-site-containing mRNAs can accept Sm-rings, expanding the known roles of Sm proteins.
• The findings suggest a novel mechanism for Sm protein regulation of cytoplasmic mRNAs.
• Reduced Sm-ring assembly on mRNAs may contribute to the pathogenesis of Spinal Muscular Atrophy (SMA).