A defective splicing machinery promotes senescence through MDM4 alternative splicing

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology
Aging Cell Pub Date : 2024-08-08 DOI:10.1111/acel.14301
Mathieu Deschênes, Mathieu Durand, Marc-Alexandre Olivier, Alicia Pellerin-Viger, Francis Rodier, Benoit Chabot
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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.

Abstract Image

Abstract Image

剪接机制缺陷通过 MDM4 替代剪接促进衰老。
剪接机制的缺陷与包括癌症在内的多种疾病有关。我们观察到,在经历复制衰老、压力诱导衰老和端粒解封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量普遍减少。剪接抑制剂herboxidiene和pladienolide B诱导正常细胞系和癌细胞系衰老,支持剪接缺陷导致衰老的观点。此外,耗尽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的替代剪接转变有关。当剪接被抑制、剪接体成分被耗尽时,MDM4剪接转变再现。虽然降低内源性MDM4的水平会促进衰老和细胞存活,而与MDM4-S的表达状态无关,但增加MDM4-S也会提高细胞存活率。总之,我们的研究证实剪接缺陷会调节MDM4的替代剪接,从而促进衰老和细胞存活。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
期刊介绍: Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.
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