Gene self-control: when pre-mRNA splicing variants become competing endogenous RNAs

Since Richard J. Roberts and Phillip A. Sharp discovered split genes (genes are interrupted by RNA-encoding regions called exons and non-coding segments called introns in eukaryotic genome) in 1970’s, scientists have been finding many genes can generate more than one mRNA transcripts through AS (alternative splicing, e.g., by different exon-exon combination). This AS strategy increases protein repertoire, encodes proteins with diverse and sometimes even antagonistic activities (Kelemen et al., 2013). A new study led by Dr. Kazuhito Tomizawa and first author Bo Zhou from Kumamoto University in Japan reports that CDKAL1-v1 (Cdk5 Regulator Subunit Associated Protein 1-Like), one splicing variant of CDKAL1, has no coding ability but acts as a miRNA sponge RNA, which regulates its full-length CDKAL1 protein (Zhou et al., 2014). Their results give us a unique paradigm of how AS possesses a regulatory role in controlling gene expression. In addition to functioning as an “internal paralog” to deliver protein-coding message (Modrek and Lee, 2003), the main well-known mechanism of gene regulation by AS is alternative splicingcoupled nonsense-mediated decay (ASNMD). Briefly, Pre-mRNA alternative splicing creates unstable mRNA isoforms with PTC (premature termination codon). Generally, if a PTC site is more than ∼50 nucleotides upstream of the last exon-exon junction, this RNA isoform will be degraded by NMD, an RNA surveillance pathway to clean up splicing errors which may lead to damaging truncated proteins (Sibley, 2014). For example, PTBP1 (polypyrimidine tract-binding protein 1) is one typical splicing regulator; it can regulate its own gene level through PTBP1-dependent exon 11 skipping to generate an AS-NMD transcript (Wollerton et al., 2004). The auto regulation through this negative-feedback loop fine-tunes PTBP1 protein level in normal