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- Title
CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor.
- Authors
Funnell, Tyler; Tasaki, Shinya; Oloumi, Arusha; Araki, Shinsuke; Kong, Esther; Yap, Damian; Nakayama, Yusuke; Hughes, Christopher S.; Cheng, S.-W. Grace; Tozaki, Hirokazu; Iwatani, Misa; Sasaki, Satoshi; Ohashi, Tomohiro; Miyazaki, Tohru; Morishita, Nao; Morishita, Daisuke; Ogasawara-Shimizu, Mari; Ohori, Momoko; Nakao, Shoichi; Karashima, Masatoshi
- Abstract
CDC-like kinase phosphorylation of serine/arginine-rich proteins is central to RNA splicing reactions. Yet, the genomic network of CDC-like kinase-dependent RNA processing events remains poorly defined. Here, we explore the connectivity of genomic CDC-like kinase splicing functions by applying graduated, short-exposure, pharmacological CDC-like kinase inhibition using a novel small molecule (T3) with very high potency, selectivity, and cell-based stability. Using RNA-Seq, we define CDC-like kinase-responsive alternative splicing events, the large majority of which monotonically increase or decrease with increasing CDC-like kinase inhibition. We show that distinct RNA-binding motifs are associated with T3 response in skipped exons. Unexpectedly, we observe dose-dependent conjoined gene transcription, which is associated with motif enrichment in the last and second exons of upstream and downstream partners, respectively. siRNA knockdown of CLK2-associated genes significantly increases conjoined gene formation. Collectively, our results reveal an unexpected role for CDC-like kinase in conjoined gene formation, via regulation of 3′-end processing and associated splicing factors. The phosphorylation of serine/arginine-rich proteins by CDC-like kinase is a central regulatory mechanism for RNA splicing reactions. Here, the authors synthesize a novel small molecule CLK inhibitor and map CLK-responsive alternative splicing events and discover an effect on conjoined gene transcription.
- Publication
Nature Communications, 2017, Vol 8, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-016-0008-7