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Role of Retinoic Acid Receptor-γ in DNA Damage-Induced Necroptosis

Chamila Kadigamuwa1, Swati Choksi1, Qing Xu1

  • 1Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA.

Iscience
|July 1, 2019
PubMed

Insights

Retinoic acid receptor gamma (RARγ) is crucial for DNA damage-induced necroptosis, a programmed cell death pathway. Loss of RARγ prevents this cell death and impacts skin cancer development.

Area of Science:

  • Molecular Biology
  • Cell Death Mechanisms
  • Cancer Biology

Background:

  • DNA-damaging agents, common chemotherapeutics, induce programmed cell death (apoptosis, necroptosis).
  • The precise molecular mechanisms underlying DNA damage-induced cell death remain incompletely elucidated.
  • Understanding these pathways is vital for cancer therapy and disease progression insights.

Purpose of the Study:

  • To investigate the role of Retinoic acid receptor gamma (RARγ) in DNA damage-induced programmed cell death.
  • To elucidate the specific cell death pathways regulated by RARγ in response to DNA damage.
  • To explore the involvement of RARγ in skin cancer development.

Main Methods:

  • Utilized DNA-damaging agents to induce cell death in cellular models.
  • Assessed apoptosis and necroptosis pathways, including the RIPK1/RIPK3 complex formation.
  • Employed RARγ1 knockout mice and human squamous cell carcinoma biopsies for in vivo and clinical relevance.

Main Results:

  • Loss of RARγ completely abolished DNA damage-induced necroptosis.
  • Cells lacking RARγ exhibited reduced susceptibility to extrinsic apoptosis but unaffected intrinsic apoptosis.
  • RARγ was demonstrated to be essential for the formation of the RIPK1/RIPK3 death complex (Ripoptosome) upon DNA damage.
  • RARγ was implicated in skin cancer development, as evidenced by studies in knockout mice and human biopsies.

Conclusions:

  • RARγ is a critical mediator of DNA damage-induced necroptosis.
  • RARγ's function in regulating cell death pathways is significant for understanding cancer biology.
  • Targeting RARγ may offer novel therapeutic strategies for DNA damage-related conditions and skin cancers.
Keywords:
BiochemistryBiological SciencesCell BiologyMolecular Biology

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