有缺陷的剪接机械通过MDM4替代剪接促进衰老
A defective splicing machinery promotes senescence through MDM4 alternative splicing
影响因子:7.10000
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
摘要
剪接机制中的缺陷与包括癌症在内的各种疾病有关。我们观察到剪接组成分和剪接调节剂的表达总体下降，该细胞系经历了复制，应激诱导和端粒诱导的衰老。支持有缺陷的剪接有助于衰老，剪接抑制剂Herbasidiene和Pladienolide B诱导正常和癌细胞系诱导衰老的观点。此外，耗尽的个体剪接体成分也促进了衰老。所有衰老类型都与从MDM4-FL变体到MDM4-S的替代剪接过渡有关。抑制剪接时复制MDM4剪接移位，并耗尽剪接组成分。尽管内源性MDM4的水平降低了与MDM4-S表达状态无关的衰老和细胞存活，但通过增加MDM4-S也可以提高细胞存活。总体而言，我们的工作确定剪接缺陷调节MDM4的替代剪接以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.