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Guardian of the Transcriptome

Mystified by the reasons for the differing amounts of snRNPs (specialized bits of RNA and protein) present in cells needed to make up the editing machinery, particularly one called the U1 snRNP, which is more abundant than any of the other components of the spliceosome, Gideon Dreyfuss, PhD, professor of Biochemistry and Biophysics, "knocked down" U1 in an immortal cells to see the effects on transcription when it was gone. He found not only a great increase in unspliced RNA transcripts, but that transcription of most of the genes had stopped too early, with a process called cleavage and polyadenylation kicking in prematurely. Rather than happening near the end of the transcription process as it should, cleavage/polyadenylation was happening too soon, preventing the transcription of proper, functional mRNA strands.  It was a completely unexpected finding, but perfectly explains what were previously believed to be "excessive" levels of U1 in the cell. Along with its normal function as part of the spliceosome, it serves as the true "guardian of the transcriptome."

In 2008, two years before his discovery the importance of U1, Dreyfuss found another important snRNP-related function. One of the major proteins responsible for the creation of snRNPs is called SMN (Survival of Motor Neuron), and is part of an entire SMN complex.  But the SMN protein does more than simply help assemble the snRNPs needed for RNA transcription.  The Dreyfuss lab looked at both cultured cells and mice in which the SMN protein had been knocked out, and saw that both the levels of snRNPs and the properly transcribed mRNAs they normally produce were greatly reduced. Deficiency of SMN is already known to cause the degenerative neurological disease spinal muscular atrophy, but these findings point to a more general consequence of SMN deficiency: disruption of the transcriptome and splicing process in all cells, not just motor neuron types. 

The U1 snRNP may be the primary component of the major spliceosome and the "guardian of the transcriptome," but most recently, the Dreyfuss lab uncovered that an almost-ignored component of the minor spliceosome -- a protein component called U6atac-- is much more significant than anyone had believed. Most of the grunt work of "editing" genes as they are transcribed from RNA into DNA is done by the major spliceosome, so much so that scientists have been puzzled by the evolutionary persistence of its seemingly superfluous minor sister U6atac.

But Dreyfuss found that U6atac is highly unstable in the cell, and that its levels act as a sort of switch to control the expression, and thus the mRNA transcription, of literally hundreds of minor genes that contain minor introns (non-coding sequences).  He also found that a particular signaling pathway, which activates when a cell is subjected to such stressors as heat or ultraviolet radiation, is only one of many possible ways in which U6atac levels are modulated and thus affect cell splicing and mRNA transcription.