An extensive program of periodic alternative splicing linked to cell cycle progression.

Daniel Dominguez,Yi-Hsuan Tsai,Yang Wang,Benjamin J Blencowe,Zefeng Wang,Robert Weatheritt

doi:10.7554/elife.10288

Daniel Dominguez, Yi-Hsuan Tsai + Show 4 more

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https://doi.org/10.7554/elife.10288

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Abstract

Progression through the mitotic cell cycle requires periodic regulation of gene function at the levels of transcription, translation, protein-protein interactions, post-translational modification and degradation. However, the role of alternative splicing (AS) in the temporal control of cell cycle is not well understood. By sequencing the human transcriptome through two continuous cell cycles, we identify ~1300 genes with cell cycle-dependent AS changes. These genes are significantly enriched in functions linked to cell cycle control, yet they do not significantly overlap genes subject to periodic changes in steady-state transcript levels. Many of the periodically spliced genes are controlled by the SR protein kinase CLK1, whose level undergoes cell cycle-dependent fluctuations via an auto-inhibitory circuit. Disruption of CLK1 causes pleiotropic cell cycle defects and loss of proliferation, whereas CLK1 over-expression is associated with various cancers. These results thus reveal a large program of CLK1-regulated periodic AS intimately associated with cell cycle control.

Highlights

Alternative splicing (AS) is a critical step of gene regulation that greatly expands proteomic diversity
We further demonstrate that a significant fraction of the periodic AS events is regulated by the Serine-Arginine rich proteins (SR) protein kinase, CDC-like kinase 1 (CLK1), and that CLK itself is subject to cell cycle-dependent regulation
We observed that CLK1 inhibition prevents its turnover after the G2/M phase for both endogenous and exogenously expressed kinases (Figure 2F and Figure 2—figure supplement 2E). These results provide strong evidence that CLK1 protein levels are controlled by ubiquitin-mediated proteolysis in a cell cycle stage-specific manner, and that an activitydependent negative feedback loop is required for this periodic regulation

Summary

Introduction

Alternative splicing (AS) is a critical step of gene regulation that greatly expands proteomic diversity. Alterations in splicing factor expression have been observed in many cancers and are thought to activate cancer-specific splicing programs that control cell cycle progression, cellular proliferation and migration (David and Manley, 2010; Oltean and Bates, 2014). Consistent with these findings, several splicing factors function as oncogenes or tumor suppressors (Karni et al, 2007; Wang et al, 2014), and cancerspecific splicing alterations often affect genes that function in cell cycle control (Tsai et al, 2015)

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