Splicing of ultraconserved poison exons controls mitotic fidelity and stem cell viability
Leclair, N. K.; Brugiolo, M.; Walawalkar, I.; Yurieva, M.; Kang, H. G.; Englander, R.; Ryan, M.; Heffner, C.; McDonough, J. A.; Skarnes, W. C.; Murray, S. C.; Anczukow, O.
Show abstract
SR proteins are essential splicing regulators whose expression is controlled in part through poison exons (PEs) -- ultraconserved non-coding exons that trigger nonsense-mediated decay -- yet the biological functions of these elements remain undefined. Here, we show that homozygous deletion of SRSF3-PE or TRA2{beta}-PE is selected against in mouse embryos and human induced pluripotent stem cells (iPSCs), and that conditional PE deletion causes apoptotic death in iPSCs but is tolerated in post-mitotic neurons, revealing a proliferative-state-specific requirement. Mechanistically, PE deletion elevates SR protein levels, triggers widespread splicing dysregulation, and disrupts the correct splicing of a mitotic gene network associated with spindle defects and mitotic errors. These findings establish ultraconserved poison exons as essential regulators of mitotic splicing fidelity and stem cell viability.
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