Pre-mRNA splice sites and splicing regulatory elements (SREs)

Pre-mRNA splice sites and splicing regulatory elements (SREs) are critical cis-acting sequences within precursor messenger RNA that govern the precise removal of introns and the ligation of exons (Wang & Burge, 2008, PubMed: 18691972). These elements, which include 5' and 3' splice sites as well as exonic and intronic enhancers and silencers, serve as binding platforms for the spliceosome and various auxiliary RNA-binding proteins (Lee & Rio, 2015, PubMed: 25585445). Mutations or variations in these sequences can lead to aberrant splicing, resulting in non-functional proteins or the loss of essential gene products, which underlies numerous genetic disorders such as Spinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD) (Singh & Singh, 2018, PubMed: 29445235). Therapeutic intervention at these sites is achieved through the use of antisense oligonucleotides (ASOs) or small molecule splicing modulators like Risdiplam (Ratni et al., 2018, PubMed: 30044102). These therapies work by either masking inhibitory sequences to promote exon inclusion or blocking splice sites to induce exon skipping, thereby restoring the reading frame or increasing the production of functional protein isoforms (Havens & Hastings, 2016, PubMed: 27108283). This target class represents a significant frontier in precision medicine, particularly for rare genetic diseases (Scott & Hafner, 2021, PubMed: 33859065).

Other names

Splice sitesCis-acting splicing elementsExonic splicing enhancers (ESE)Exonic splicing silencers (ESS)Intronic splicing enhancers (ISE)Intronic splicing silencers (ISS)Splice junctionSplicing motifs

Drugs targeting these elements typically act as splicing modulators. Antisense oligonucleotides (ASOs) bind to specific regulatory sequences via Watson-Crick base pairing to sterically block the binding of splicing factors or the spliceosome, thereby inducing exon skipping or inclusion (Havens & Hastings, 2016, PubMed: 27108283). Small molecules can also target these sites by stabilizing specific RNA-protein complexes, such as the U1 snRNP at the 5' splice site, enhancing the recognition of weak splice sites by the splicing machinery (Campagne et al., 2019, PubMed: 31019236).