缺陷的剪接机制通过MDM4可变剪接促进衰老

A defective splicing machinery promotes senescence through MDM4 alternative splicing

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AGING CELL

影响因子:7.1

分区:医学1区 Top / 老年医学1区细胞生物学2区

发表日期:2024 Nov

作者: Mathieu Deschênes, Mathieu Durand, Marc-Alexandre Olivier, Alicia Pellerin-Viger, Francis Rodier, Benoit Chabot

DOI: 10.1111/acel.14301

摘要

剪接机制的缺陷与多种疾病有关，包括癌症。我们观察到在人类细胞系中，经历复制性、应激诱导和端粒未盖帽诱导的衰老过程中，剪接体组分和剪接调控因子的表达普遍下降。支持剪接缺陷促进衰老的观点，剪接抑制剂Herboxidiene和Pladienolide B在正常和癌细胞系中诱导衰老。此外，耗竭个别剪接体组分也促进了衰老。所有的衰老类型都伴随着MDM4全长（FL）变体向MDM4-S的可变剪接转换。该剪接变化在用剪接抑制剂或耗竭剪接体组分时得以重现。虽然降低内源性MDM4水平可在不依赖MDM4-S表达状态下促进衰老和细胞存活，但增加MDM4-S也能改善细胞存活。总体而言，我们的研究证实，剪接缺陷通过调节MDM4的可变剪接促进衰老和细胞存活。

Abstract

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.