CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor

Tyler Funnell, Shinya Tasaki, Arusha Oloumi, Shinsuke Araki, Esther Kong, Damian Yap, Yusuke Nakayama, Christopher S. Hughes, S.-W. Grace Cheng, Hirokazu Tozaki, Misa Iwatani, Satoshi Sasaki, Tomohiro Ohashi, Tohru Miyazaki, Nao Morishita, Daisuke Morishita, Mari Ogasawara-Shimizu, Momoko Ohori, Shoichi Nakao, Masatoshi Karashima, Masaya Sano, Aiko Murai, Toshiyuki Nomura, Noriko Uchiyama, Tomohiro Kawamoto, Ryujiro Hara, Osamu Nakanishi, Karey Shumansky, Jamie Rosner, Adrian Wan, Steven McKinney, Gregg B. Morin, Atsushi Nakanishi, Sohrab Shah, Hiroyoshi Toyoshiba () and Samuel Aparicio ()
Additional contact information
Tyler Funnell: Department of Molecular Oncology, BC Cancer Agency
Shinya Tasaki: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Arusha Oloumi: Department of Molecular Oncology, BC Cancer Agency
Shinsuke Araki: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Esther Kong: Department of Molecular Oncology, BC Cancer Agency
Damian Yap: Department of Molecular Oncology, BC Cancer Agency
Yusuke Nakayama: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Christopher S. Hughes: Michael Smith Genome Sciences Centre, BC Cancer Agency
S.-W. Grace Cheng: Michael Smith Genome Sciences Centre, BC Cancer Agency
Hirokazu Tozaki: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Misa Iwatani: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Satoshi Sasaki: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Tomohiro Ohashi: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Tohru Miyazaki: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Nao Morishita: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Daisuke Morishita: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Mari Ogasawara-Shimizu: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Momoko Ohori: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Shoichi Nakao: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Masatoshi Karashima: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Masaya Sano: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Aiko Murai: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Toshiyuki Nomura: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Noriko Uchiyama: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Tomohiro Kawamoto: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Ryujiro Hara: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Osamu Nakanishi: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Karey Shumansky: Department of Molecular Oncology, BC Cancer Agency
Jamie Rosner: Department of Molecular Oncology, BC Cancer Agency
Adrian Wan: Department of Molecular Oncology, BC Cancer Agency
Steven McKinney: Department of Molecular Oncology, BC Cancer Agency
Gregg B. Morin: Michael Smith Genome Sciences Centre, BC Cancer Agency
Atsushi Nakanishi: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Sohrab Shah: Department of Molecular Oncology, BC Cancer Agency
Hiroyoshi Toyoshiba: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Samuel Aparicio: Department of Molecular Oncology, BC Cancer Agency

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-016-0008-7

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