Splicing regulator

Splicing regulators are a diverse group of proteins and ribonucleoprotein complexes, including SR proteins, hnRNPs, and the spliceosome itself, that orchestrate the removal of introns and the joining of exons in pre-mRNA [1, 3]. This process, known as alternative splicing, allows a single gene to produce multiple protein isoforms, significantly expanding the functional diversity of the proteome [2, 8]. Dysregulation of splicing regulators, often through mutations or expression changes, is a hallmark of various diseases, particularly cancers like myelodysplastic syndromes and rare genetic disorders like spinal muscular atrophy [3, 9]. Therapeutic strategies targeting these regulators include small-molecule inhibitors of the spliceosome, molecular glues that induce the degradation of specific splicing factors, and splicing modifiers that correct aberrant splicing events in specific transcripts [4, 5, 7]. While promising, targeting the core splicing machinery often faces challenges related to systemic toxicity due to the essential nature of splicing in all cells [1, 5].

Other names

Splicing factorRNA-binding protein (RBP)Splicing modifier targetSpliceosome componentAlternative splicing regulator

Splicing regulators are targeted by small molecules or antisense oligonucleotides to modulate the inclusion or exclusion of specific exons in pre-mRNA. This is achieved through direct inhibition of the spliceosome (e.g., SF3B1 inhibitors), molecular glue-induced degradation of specific splicing factors (e.g., RBM39 degraders), or splicing modifiers that stabilize the interaction between the spliceosome and specific pre-mRNA sequences (e.g., SMN2 splicing modifiers).