An Alternative Splicing Network Links Cell-Cycle Control to Apoptosis

SummaryAlternative splicing is a vast source of biological regulation and diversity that is misregulated in cancer and other diseases. To investigate global control of alternative splicing in human cells, we analyzed splicing of mRNAs encoding Bcl2 family apoptosis factors in a genome-wide siRNA screen. The screen identified many regulators of Bcl-x and Mcl1 splicing, notably an extensive network of cell-cycle factors linked to aurora kinase A. Drugs or siRNAs that induce mitotic arrest promote proapoptotic splicing of Bcl-x, Mcl1, and caspase-9 and alter splicing of other apoptotic transcripts. This response precedes mitotic arrest, indicating coordinated upregulation of prodeath splice variants that promotes apoptosis in arrested cells. These shifts correspond to posttranslational turnover of splicing regulator ASF/SF2, which directly binds and regulates these target mRNAs and globally regulates apoptosis. Broadly, our results reveal an alternative splicing network linking cell-cycle control to apoptosis.

Graphical AbstractFigure optionsDownload high-quality image (143 K)Download as PowerPoint slideHighlights
► Functional genomic screen defines regulators of alternative splicing in apoptosis
► Disruption of cycle factors promotes coordinated proapoptotic mRNA splicing
► A major RNA-binding protein, ASF/SF2, mediates this proapoptotic splicing network