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A Defective Splicing Machinery Promotes Senescence through MDM4 Alternative Splicing

ABSTRACT: Defects in the splicing machinery have been implicated in various diseases, including cancer. We identified a general reduction in the expression spliceosome components and splicing regulators in human cell lines undergoing replicative, stress-induced and telomere uncapping-induced senescence. Supporting the notion that defective splicing contributes to senescence, we showed that the splicing inhibitors herboxidiene and pladienolide B induce senescence both in normal and cancer cell lines. Furthermore, the individual depletion of several spliceosome components also promoted senescence. We noted an alternative splicing shift in MDM4, from the full-length MDM4-FL variant to MDM4-S during replicative and stress-induced senescence. This shift was replicated by splicing inhibition and the depletion of individual spliceosome components. Importantly, decreasing the level of MDM4-FL promoted senescence, while cell survival was improved both by reducing the level of MDM4-FL and by overexpressing MDM4-S. Overall, our work establishes that defects in the splicing machinery alter the alternative splicing of MDM4 to promote senescence.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245356 | GEO | 2024/10/11

REPOSITORIES: GEO

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A Defective Splicing Machinery Promotes Senescence through MDM4 Alternative Splicing

Project description:A Defective Splicing Machinery Promotes Senescence through MDM4 Alternative Splicing

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Splicing modulation increases BCL2 dependence and sensitizes Multiple Myeloma cells to Venetoclax

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Functional splicing network reveals extensive regulatory plasticity of the core Spliceosomal machinery

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SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes

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Competition between pre-mRNAs for a limiting splicing machinery drives global changes in splicing

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Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery (BeadChip)

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