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Autoregulation of the human splice factor kinase CLK1 through exon skipping and intron retention

Uzor, Simon; Zorzou, Panagiota; Bowler, Elisabeth; Porazinski, Sean; Wilson, Ian D; Ladomery, Michaek


Simon Uzor

Panagiota Zorzou

Elisabeth Bowler

Sean Porazinski


© 2018 Elsevier B.V. Alternative splicing is a key process required for the regulation of gene expression in normal development and physiology. It is regulated by splice factors whose activities are in turn regulated by splice factor kinases and phosphatases. The CDC-like protein kinases are a widespread family of splice factor kinases involved in normal physiology and in several diseases including cancer. In humans they include the CLK1, CLK2, CLK3 and CLK4 genes. The expression of CLK1 is regulated through alternative splicing producing both full-length catalytically active and truncated catalytically inactive isoforms, CLKT1 (arising from exon 4 skipping) and CLKT2 (arising from intron 4 retention). We examined CLK1 alternative splicing in a range of cancer cell lines, and report widespread and highly variable rates of exon 4 skipping and intron 4 retention. We also examined the effect of severe environmental stress including heat shock, osmotic shock, and exposure to the alkaloid drug harmine on CLK1 alternative splicing in DU145 prostate cancer cells. All treatments rapidly reduced exon 4 skipping and intron 4 retention, shifting the balance towards full-length CLK1 expression. We also found that the inhibition of CLK1 with the benzothiazole TG003 reduced exon 4 skipping and intron 4 retention suggesting an autoregulatory mechanism. CLK1 inhibition with TG003 also resulted in modified alternative splicing of five cancer-associated genes.


Uzor, S., Zorzou, P., Bowler, E., Porazinski, S., Wilson, I. D., & Ladomery, M. (2018). Autoregulation of the human splice factor kinase CLK1 through exon skipping and intron retention. Gene, 670, 46-54.

Journal Article Type Article
Acceptance Date May 23, 2018
Online Publication Date May 24, 2018
Publication Date Sep 5, 2018
Journal Gene
Print ISSN 0378-1119
Electronic ISSN 1879-0038
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 670
Pages 46-54
Keywords CDC-like protein kinases, CLK1, alternative splicing, cassette exons, intron retention, detained introns, CLK1 inhibitor TG003, harmine
Public URL
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Additional Information Additional Information : This is the author's accepted manuscript. The final published version is available here:


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