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Cytoplasmic DNA in cancer cells: Several pathways that potentially limit DNase2 and TREX1 activities

Roy Anindya1

  • 1Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Sangareddy 502284, India.

Biochimica Et Biophysica Acta. Molecular Cell Research
|April 30, 2022
PubMed

Insights

Cytoplasmic DNA in tumor cells triggers immune responses. This review explores how impaired DNA degradation by DNase2 and TREX1 contributes to aggressive tumors and chronic inflammation.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Cytoplasmic DNA in tumor cells activates type-I IFNs via cGAS-STING, mimicking viral infection responses.
  • While cytosolic DNA can induce senescence and immune surveillance, its accumulation in metastatic tumors is linked to aggressive disease.
  • Aberrant type I IFN pathway activation is a hallmark of aggressive tumors, suggesting a role for cytoplasmic DNA.

Purpose of the Study:

  • To review the connection between impaired function of deoxyribonucleases (DNase2 and TREX1) and innate immune signaling in cancer.
  • To summarize mechanisms limiting DNase2 and TREX1 activity in tumor cells.
  • To elucidate the contribution of cytoplasmic DNA accumulation to chronic inflammation in cancer.

Main Methods:

  • Literature review of recent research on cytoplasmic DNA, innate immunity, and cancer.
  • Analysis of the roles of DNase2 and TREX1 in targeting cytoplasmic DNA.
  • Exploration of mechanisms contributing to chronic inflammation in tumors.

Main Results:

  • Impaired function of DNase2 and TREX1 leads to cytoplasmic DNA accumulation.
  • This accumulation aberrantly activates the type I IFN pathway, promoting aggressive tumor phenotypes.
  • Mechanisms limiting DNase2/TREX1 activity contribute to chronic inflammation in tumor microenvironments.

Conclusions:

  • The inability of DNase2 and TREX1 to clear cytoplasmic DNA is a key factor in tumor-associated inflammation and aggressive cancer.
  • Understanding these mechanisms offers potential therapeutic targets for managing aggressive tumors and associated inflammation.
Keywords:
Cytoplasmic DNACytosolic DNADNASE2ExonucleaseMicronucleiTREX1

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