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A defective splicing machinery promotes senescence through MDM4 alternative splicing

Mathieu Deschênes1, Mathieu Durand1, Marc-Alexandre Olivier2,3

  • 1Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.

Aging Cell
|August 9, 2024
PubMed

Insights

Splicing defects reduce spliceosome components, triggering cellular senescence. This process alters MDM4 splicing, promoting both senescence and cell survival, impacting diseases like cancer.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Defects in the splicing machinery are linked to various diseases, including cancer.
  • Cellular senescence is a state of irreversible growth arrest with implications in aging and disease.

Purpose of the Study:

  • To investigate the role of splicing defects in cellular senescence.
  • To explore the impact of spliceosome component reduction and splicing inhibition on senescence.
  • To determine the specific alternative splicing events associated with senescence and their effect on cell survival.

Main Methods:

  • Analysis of spliceosome component expression in senescent human cell lines.
  • Induction of senescence using splicing inhibitors (herboxidiene, pladienolide B) and depletion of spliceosome components.
  • Investigation of alternative splicing of the MDM4 gene (MDM4-FL and MDM4-S variants).
  • Assessment of cell survival under varying MDM4 levels and MDM4-S expression.

Main Results:

  • A general reduction in spliceosome components and splicing regulators was observed in replicative, stress-induced, and telomere uncapping-induced senescence.
  • Splicing inhibitors and depletion of spliceosome components induced senescence in normal and cancer cells.
  • All senescence types exhibited a shift in MDM4 alternative splicing from the full-length (MDM4-FL) to the short (MDM4-S) variant.
  • Decreasing endogenous MDM4 promoted senescence and cell survival, while increasing MDM4-S also improved cell survival.

Conclusions:

  • Splicing defects are a significant factor in promoting cellular senescence.
  • The alternative splicing of MDM4 is modulated by splicing defects, contributing to senescence and cell survival.
  • Targeting splicing pathways may offer therapeutic strategies for diseases associated with senescence and cancer.
Keywords:
MDM4RNAalternative splicingsenescencespliceosomesplicing factors

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