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CSB promoter downregulation via histone H3 hypoacetylation is an early determinant of replicative senescence

Clément Crochemore1,2, Cristina Fernández-Molina1,2,3, Benjamin Montagne1,2

  • 1Institut Pasteur, Stem Cells and Development, Department of Developmental and Stem Cell Biology, 75015, Paris, France.

Nature Communications
|December 8, 2019
PubMed

Insights

Depleting Cockayne syndrome B (CSB) protein triggers early cellular senescence by affecting p21. This discovery links progeroid factors to normal human aging and age-related diseases.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Cellular senescence is linked to aging and age-related diseases.
  • The role of progeroid factors in inducing senescence in normal cells is not well understood.

Purpose of the Study:

  • To investigate if Cockayne syndrome B (CSB) protein depletion triggers cellular senescence in normal cells.
  • To elucidate the molecular mechanisms underlying CSB's role in senescence and its connection to Cockayne syndrome (CS).

Main Methods:

  • Depletion of CSB protein in human cells.
  • Analysis of p21-dependent senescence markers.
  • Assessment of HTRA3 protease expression and mitochondrial function.
  • Investigation of CSB binding to the p21 promoter.
  • Evaluation of oxidative/nitrosative stress impact.

Main Results:

  • CSB depletion is the earliest known trigger of p21-dependent replicative senescence.
  • CSB depletion increases HTRA3 protease, leading to mitochondrial impairments linked to CS.
  • CSB binds the p21 promoter, downregulating transcription and blocking senescence independently of p53 and DNA repair.
  • Reduced oxidative stress partially rescues HTRA3 accumulation and senescence.

Conclusions:

  • A novel CSB/p21 axis acts as a barrier to replicative senescence.
  • This study links a progeroid factor (CSB) to the process of human aging.
  • Findings provide insights into Cockayne syndrome pathogenesis and cellular senescence.

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