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Penn study identifies molecular guardian of cell's RNA

When most genes are transcribed, the nascent RNAs they produce are not quite ready to be translated into proteins - they have to be processed first. One of those processes is called splicing, a mechanism by which non-coding gene sequences are removed and the remaining protein-coding sequences are joined together to form a final, mature messenger RNA (mRNA), which contains the recipe for making a protein.

For years, researchers have understood the roles played by the molecular machines that carry out the splicing process. But, as it turns out, one of those familiar components plays a new, and altogether unexpected role.

As senior author Gideon Dreyfuss, PhD, the Isaac Norris Professor of Biochemistry and Biophysics at the University of Pennsylvania School of Medicine and colleagues report in Nature, one of the splicing machinery's components called U1 has a second, equally important role in gene expression: To enable gene sequences to be read out into their RNA transcripts in their entirety, rather than have that process prematurely stopped. Dreyfuss is also a Howard Hughes Medical Institute Investigator.

The researchers revealed an unexpected function for U1 in protecting mRNA transcripts from premature termination in addition to and independent of its role in splicing.

As Dreyfuss puts it, "U1 is a guardian of the transcriptome." The transcriptome is the set of all RNA molecules in one cell.

U1 is one of a collection of RNA-protein complexes, called snRNPs, that recognize splicing junctions, excise non-coding gene sequences called introns, and join the remaining coding sequences called exons together. The Dreyfuss team previously showed that loss of SMN, a protein that helps assemble snRNPs and is deficient in individuals with the common neurodegenerative disease spinal muscular atrophy (SMA), results in altered snRNP levels and abnormal splicing.

SMN deficiency affects all snRNPs to one degree or another. The Dreyfuss team wanted to find out what would happen if just one snRNP was missing. They started with U1.

The team's expectation was that they would detect an increase in unspliced RNA transcripts, and indeed they saw evidence of that. But, to their surprise, the majority of the genes produced a very different and striking result. Their transcripts terminated prematurely and abruptly, generally within a relatively short distance from the transcription start site of the gene.

When they sequenced the ends of the resulting truncated RNAs, they found that they had been prematurely cleaved and tagged with a long string of nucleotide building blocks called adenine. This string is a hallmark of a process called cleavage-and-polyadenylation, which normally occurs at the end of a gene's RNA transcript. The lack of U1 was causing the cleavage/polyadenylation machinery to kick into gear early.
 
 

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