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Updated: Aug 15, 2025

Techniques to Induce and Quantify Cellular Senescence
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Techniques to Induce and Quantify Cellular Senescence

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RNaseH2A downregulation drives inflammatory gene expression via genomic DNA fragmentation in senescent and cancer

Sho Sugawara1, Ryo Okada1,2, Tze Mun Loo1

  • 1Division of Cellular Senescence, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, 135-8550, Japan.

Communications Biology
|December 28, 2022
PubMed

Insights

Cellular senescence triggers the senescence-associated secretory phenotype (SASP) via nucleotide buildup. Reduced RNaseH2A expression drives this, promoting age-related diseases and cancer progression.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • Cellular senescence, induced by oncogenic stress, contributes to aging and disease via the senescence-associated secretory phenotype (SASP).
  • SASP activation is linked to cytoplasmic nucleic acid sensors, but the mechanism of nucleotide ligand accumulation in senescent cells remains unknown.

Purpose of the Study:

  • To elucidate the molecular mechanism of nucleotide ligand accumulation in senescent cells.
  • To investigate the role of RNaseH2A in regulating SASP and its implications in aging and cancer.

Main Methods:

  • Investigated the regulation of RNaseH2A expression by E2F transcription factors during cellular senescence.
  • Analyzed RNaseH2A levels in aged mouse tissues and Werner syndrome patient cells.
  • Utilized an auxin-inducible degron system to degrade RNaseH2A and assess its effects on nucleotide accumulation, SASP induction, and cancer cell metastasis.

Main Results:

  • RNaseH2A expression, which removes ribonucleoside monophosphates (rNMPs) from the genome, decreases during cellular senescence.
  • Accumulated rNMPs lead to DNA fragmentation and aberrant activation of cytoplasmic nucleic acid sensors, inducing SASP.
  • Decreased RNaseH2A was observed in aged tissues and Werner syndrome cells; its degradation promoted cancer cell metastasis.

Conclusions:

  • RNaseH2A downregulation is a key driver of SASP through nucleotide ligand accumulation.
  • This mechanism contributes to the pathology of senescent, progeroid, and cancer cells.
  • Targeting RNaseH2A may offer therapeutic strategies for age-related diseases and cancer.

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