Exploiting the Hidden Treasure of Detained Introns

Abstract

Many mammalian genes contain poorly spliced introns, resulting in nuclear detention of partially spliced transcripts, which may be exploited to modulate gene expression. In this issue of Cancer Cell, Braun et al. report that the arginine methyltransferase PRMT5 is critical for tumor cell proliferation by regulating numerous detained introns.

Figure 1. Exploring the Regulatory Window of Intron Retention for Cancer Therapeutics

(A) Two types of intron retention. One type is retained introns that can be exported to the cytoplasm and then degraded by nonsense-mediated decay (NMD). The other type is detained introns that remain in the nucleus, where they are either further spliced to produce fully spliced mRNAs for export or degraded by the exosome. (B) PRMT5-regulated splicing important for tumor cell proliferation. PRMT5-mediated arginine methylation enhances the functions of the core splicing machinery (e.g., snRNP components) and splicing factors (e.g., SRSF1) to promote the removal of a detained intron in ARUKB and induce Bcl-x splicing. Efficient expression of ARUKB and the production of the pro-survival Bcl-xL isoform enable cancer cells to undergo more efficient cell cycle and less apoptosis. Inhibition of PRMT5 may not only reverse these processes, but also induce a self-enforcing loop in which increased intron retention represses ARUKB expression, which may somehow destabilize SRSF1 to cause further inhibition of ARUBK splicing and also induce a switch of Bcl-x splicing to generate the pro-apoptotic Bcl-xS isoform. These events may synergistically block tumor cell proliferation and increase tumor cell death, thus achieving potent anti-tumor effects.