Fig. 3: Known mechanisms of autoregulation of splicing factors.

Splicing factors negatively autoregulate their own synthesis by promoting unproductive splicing of their own transcripts. Alternative splicing may create a full-length productive isoform that encodes a functional protein or may result in a premature termination codon (PTC). Transcripts with PTC are committed to nonsense-mediated mRNA-decay (NMD). Following events can lead to PTC: frameshift due to exon skipping; usage of an alternative 5' or 3' splice site with an in-frame PTC; frameshift due to inclusion of mutually exclusive exons (or none of them); splicing in the 3' untranslated region (UTR), at a position located >55 nucleotides downstream of the stop codon (STOP), creating a premature context that triggers NMD; retention of PTC-containing exon (also known as poison cassette exon, PCE); or retention of the intron with an in-frame PTC. Transcripts that include poison cassette exon can be NMD-resistant. In the case of SRSF7, negative autoregulation occurs due to the formation of functionally defective truncated protein or by the production of RNA isoforms, which are sequestered in the nucleus. The U1A protein is involved in autoregulation, preventing productive 3' end processing and polyadenylation. In the case of the TDP-43 splicing protein, it binds to GU-rich sequences in the 3'-UTR of its own mRNA, which causes its degradation. As an example of a positive feedback loop, the SRSF1 protein can compete with Mir505-3p for binding to its own mRNA, thereby inhibiting its own degradation. Introns are represented as black lines and exons as green boxes.