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Temporal Tracking of Cell Cycle Progression Using Flow Cytometry without the Need for Synchronization
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Cell Cycle Checkpoints Cooperate to Suppress DNA- and RNA-Associated Molecular Pattern Recognition and Anti-Tumor

Jie Chen1, Shane M Harding1, Ramakrishnan Natesan1

  • 1Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Cell Reports
|September 3, 2020
PubMed

Insights

Cell cycle arrest prevents anti-tumor immunity. Disrupting p53 and G2 checkpoints restores DNA damage signaling and immune responses in cancer cells, aiding immunotherapy design.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • Cyclic GMP-AMP synthase (cGAS) links DNA damage to immune responses.
  • Mitotic errors activate cGAS, but its role in cancer cell-intrinsic immunity is unclear.
  • Restoring inflammation in resistant cancer cells via checkpoint disruption is unknown.

Purpose of the Study:

  • Investigate if mitosis progression is required for cancer cell-intrinsic anti-tumor immunity.
  • Determine if cell cycle checkpoint disruption can restore DNA damage-induced inflammation in resistant cancer cells.

Main Methods:

  • Studied the effect of prolonged G2-mitosis arrest (via DNA damage or CDK1 inhibition) on inflammatory gene expression and anti-tumor immunity.
  • Assessed restoration of DNA damage-induced inflammatory signaling upon p53 and G2 checkpoint disruption.
  • Investigated the role of RIG-I in restored inflammatory signaling.

Main Results:

  • Prolonged G2-mitosis arrest inhibits inflammatory gene expression and immune-mediated tumor destruction.
  • Concomitant disruption of p53 and the G2 checkpoint restores DNA damage-induced inflammatory signaling.
  • Restoration of inflammatory signaling is RIG-I dependent.

Conclusions:

  • Aberrant cell cycle progression and p53 loss expand damage-associated molecular pattern recognition.
  • Findings suggest strategies to enhance anti-tumor immune responses by targeting cell cycle checkpoints and p53.
  • Links cell cycle control to immune evasion in cancer.
Keywords:
ATRDNA damageRIG-Ianti-tumor immune responsecGAScell cycle checkpointinflammatory signalingp53

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