CDC-like kinase 1 (CLK1) pre-mRNA intron 3–exon 4 splice junction (CLK1 i3-e4 junction)

The CDC-like kinase 1 (CLK1) pre-mRNA intron 3–exon 4 splice junction is a critical regulatory site involved in the autoregulation of CLK1 expression (Ninomiya et al., 2011). CLK1 is a dual-specificity kinase that phosphorylates serine/arginine-rich (SR) proteins, which are key components of the spliceosome (UniProt P23292). By modulating the splicing of its own pre-mRNA at the intron 3–exon 4 boundary, CLK1 can produce different isoforms, including those that are non-functional or subject to nonsense-mediated decay. This site has emerged as a therapeutic target for small molecule splicing modulators, such as SM08502, which promote the skipping of exon 4 (Tam et al., 2019). In cancer cells, inducing exon skipping at this junction leads to the depletion of functional CLK1 protein, resulting in disrupted splicing of multiple downstream genes essential for tumor cell survival and proliferation. Consequently, targeting this specific splice junction offers a mechanism to selectively downregulate CLK1 activity in various malignancies, including colorectal and gastrointestinal cancers. A significant therapeutic challenge is the potential for off-target splicing effects, as CLK1 and its related kinases regulate the processing of numerous transcripts across the genome.

Other names

CLK1 pre-mRNACLK1 exon 4 splice siteCLK1 intron 3-exon 4 boundaryCLK1 i3-e4 junctionCDC-like kinase 1 pre-mRNA

Splicing modulation via induction of exon skipping or intron retention to downregulate functional protein expression.