EDITOR'S CHOICE IN RNA INTERFERENCE
COURTESY OF PHILLIP DUMESIC, UCSF (Adapted from Transposon by Lauren Solomon, Broad Institute)
P.A. Dumesic et al., “Stalled spliceosomes are a signal for RNAi-mediated genome defense,” Cell, 152:957-68, 2013.
Although small interfering RNAs (siRNAs) are largely explored today for their potential in gene therapy, the phenomenon was first described in plants, which employ siRNAs to disable foreign RNA from viral infections. Researchers have since learned that siRNAs also play a role in suppressing transposable elements, which replicate and reinsert throughout the genome, occasionally disrupting the function of essential genes. Now, Hiten Madhani of the University of California, San Francisco, and colleagues have implicated the spliceosome, a molecular complex that excises introns from pre-messenger RNAs (pre-mRNAs), in siRNA-mediated suppression.
The splice of life
Like any gene, transposable elements are transcribed into pre-mRNAs that must be processed by the spliceosome. Madhani’s team noticed, however, that transposable-element pre-mRNAs appeared to be associated with spliceosomes more frequently than other pre-mRNAs.
When the researchers searched for proteins associated with the spliceosome and with siRNAs, they discovered a novel complex they dubbed spliceosome-coupled and nuclear RNAi, or SCANR, that appeared to be involved in producing siRNAs. Madhani reasoned that the spliceosome was “being used to recognize self- from nonself-DNA,” such as transposable elements. Such transcripts would have been introduced later in a cell’s evolution, and may not be optimized for the cell’s splicing machinery, causing it to stall, thereby giving SCANR more time to produce siRNA against the offending message.
The paper reveals “an unexpected and previously unappreciated way for the cell to score an RNA as ‘aberrant’ and therefore in need of silencing,” says Erik Sontheimer, a researcher at Northwestern University.