剪接机制的缺陷与多种疾病有关，包括癌症。我们观察到，在经历复制、应激诱导和端粒脱帽诱导衰老的人类细胞系中，剪接体成分和剪接调节因子的表达普遍减少。支持缺陷剪接导致衰老的观点，剪接抑制剂 Herboxidiene 和 pladienolide B 诱导正常细胞系和癌细胞系衰老。此外，消耗单个剪接体成分也会促进衰老。所有衰老类型都与从 MDM4-FL 变体到 MDM4-S 的选择性剪接转变相关。当剪接被抑制并且剪接体成分被耗尽时，MDM4 剪接移位会重现。虽然降低内源性 MDM4 水平可促进衰老和细胞存活，而与 MDM4-S 表达状态无关，但增加 MDM4-S 也可提高细胞存活率。总体而言，我们的工作确定剪接缺陷调节 MDM4 的选择性剪接以促进衰老和细胞存活。© 2024 作者。衰老细胞由解剖学会和约翰·威利出版

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.© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.