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PARP1 depletion induces RIG-I-dependent signaling in human cancer cells

Rajib Ghosh1, Sanchita Roy1, Sonia Franco1

  • 1Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.

Plos One
|March 29, 2018
PubMed

Insights

DNA repair protein PARP1 suppresses innate immune signaling. Loss of PARP1 activates interferon genes and cell senescence, particularly when combined with DNA damage, impacting aging and cancer.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • DNA Damage Response (DDR) and DNA repair pathways are critical regulators of cellular homeostasis.
  • Emerging evidence suggests these pathways also suppress innate immune signaling in human cells.

Purpose of the Study:

  • To investigate the role of the Single Strand Break (SSB) repair protein PARP1 in innate immune suppression.
  • To elucidate the mechanisms by which PARP1 depletion affects immune signaling and cellular responses.

Main Methods:

  • Depletion of PARP1 in human cells.
  • Induction of innate immune signaling via viral mimicry.
  • Analysis of interferon-stimulated genes (ISGs) and pattern recognition receptors (PRRs).
  • Investigation of the RIG-I/MAVS pathway and interferon signaling loops.

Main Results:

  • PARP1-depleted cells exhibit p21-dependent senescence or cell cycle arrest upon innate immune activation.
  • Significant induction of ISGs and PRRs (RIG-I, MDA-5, MAVS, TLR3, STING) was observed.
  • The RIG-I/MAVS pathway is essential for sustained ISG expression in PARP1-depleted cells.
  • An autocrine/paracrine loop involving interferon-alpha/beta receptor is required for persistent ISG expression.
  • Loss of PARP1 and radiation-induced DNA damage synergize to induce p21 and ISGs.

Conclusions:

  • PARP1 acts as a suppressor of innate immune signaling.
  • PARP1 depletion leads to immune activation and cellular senescence, mediated by the RIG-I/MAVS pathway and interferon signaling.
  • Combined loss of PARP1 and DNA damage exacerbates these responses, suggesting a role for PARP1 in suppressing aging, inflammation, and cancer phenotypes.

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