A defective splicing machinery promotes senescence through MDM4 alternative splicing

Defects in the splicing machinery are implicated in various diseases, including cancer. We observed a general reduction in the expression of spliceosome components and splicing regulators in human cell lines undergoing replicative, stress-induced, and telomere uncapping-induced senescence. Supporting the view that defective splicing contributes to senescence, splicing inhibitors herboxidiene, and pladienolide B induced senescence in normal and cancer cell lines. Furthermore, depleting individual spliceosome components also promoted senescence. All senescence types were associated with an alternative splicing transition from the MDM4-FL variant to MDM4-S. The MDM4 splicing shift was reproduced when splicing was inhibited, and spliceosome components were depleted. While decreasing the level of endogenous MDM4 promoted senescence and cell survival independently of the MDM4-S expression status, cell survival was also improved by increasing MDM4-S. Overall, our work establishes that splicing defects modulate the alternative splicing of MDM4 to promote senescence and cell survival. Reduced expression of spliceosome components and splicing regulators were observed in senescent cells. Splicing inhibitors and depletion of spliceosome components induced senescence, associated with an alternative splicing shift from MDM4-FL to MDM4-S. Decreasing MDM4-FL promoted senescence, while increasing MDM4-S and decreasing MDM4-FL improved cell survival.image