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Cited by 23Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsDNA Repair Mechanisms

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

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Sugawara, Sho, Okada, Ryo, Loo, Tze Mun, Tanaka, Hisamichi, Miyata, Kenichi, Chiba, Masatomo, Kawasaki, Hiroko, Katoh, Kaoru +13 more·2022·Communications Biology
DOI 10.1038/s42003-022-04369-7PMC PMC9797495
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Abstract

Cellular senescence caused by oncogenic stimuli is associated with the development of various age-related pathologies through the senescence-associated secretory phenotype (SASP). SASP is mediated by the activation of cytoplasmic nucleic acid sensors. However, the molecular mechanism underlying the accumulation of nucleotide ligands in senescent cells is unclear. In this study, we revealed that the expression of RNaseH2A, which removes ribonucleoside monophosphates (rNMPs) from the genome, is regulated by E2F transcription factors, and it decreases during cellular senescence. Residual rNMPs cause genomic DNA fragmentation and aberrant activation of cytoplasmic nucleic acid sensors, thereby provoking subsequent SASP factor gene expression in senescent cells. In addition, RNaseH2A expression was significantly decreased in aged mouse tissues and cells from individuals with Werner syndrome. Furthermore, RNaseH2A degradation using the auxin-inducible degron system induced the accumulation of nucleotide ligands and induction of certain tumourigenic SASP-like factors, promoting the metastatic properties of colorectal cancer cells. Our results indicate that RNaseH2A downregulation provokes SASP through nucleotide ligand accumulation, which likely contributes to the pathological features of senescent, progeroid, and cancer cells.

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  • Chromatin conformational changes at hSATII might promote malignant transformation or cancer progression.

    “Since previous studies have shown that elevated SASP in CAFs contributes to the development of cancers (11, 21, 41, 42), chromatin conformational changes at hSATII might promote the malignant transformation or cancer progression (Fig. 4E).”

    From Chromatin conformational changes at human satellite II contribute to the senescence phenotype in the tumor microenvironment (2023) · cites this paper as [42]

    The citation is attached to the preceding claim that SASP in cancer-associated fibroblasts (CAFs) contributes to cancer development, not to the citing authors’ proposal about hSATII. The source’s Discussion says senescent cells can promote transformation, invasion, and metastasis through SASP factors, but the passages found do not establish this specifically for CAFs. Its Results concern RNaseH2A depletion in cancer cells, not chromatin changes at hSATII; the latter is the citing authors’ own inference. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Cancer cells exhibit senescence-like phenotypes.

    “we and other groups have reported that cancer cells exhibit senescence-like phenotypes (7, 42).”

    From Chromatin conformational changes at human satellite II contribute to the senescence phenotype in the tumor microenvironment (2023) · cites this paper as [42]

    The Results section, “RNaseH2A depletion induces SASP-like gene expression in cancer cells” (page unavailable), reports a senescence-associated feature in colorectal cancer cells and organoids. That supports an example of a senescence-like phenotype, but the paper does not establish that cancer cells generally exhibit a broader range of senescence-like phenotypes. (LLM, conf=0.81)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 45

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Cited by

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Authors
Sugawara, S., Okada, R., Loo, T. M., Tanaka, H., Miyata, K., Chiba, M., Kawasaki, H., Katoh, K., Kaji, S., Maezawa, Y., Yokote, K., Nakayama, M., Oshima, M., Nagao, K., Obuse, C., Nagayama, S., Takubo, K., Nakanishi, A., Kanemaki, M. T., Hara, E., & Takahashi, A.
Affiliations
  • Japanese Foundation For Cancer Research (JP)
  • Tokyo Medical and Dental University (JP)
  • National Institute of Advanced Industrial Science and Technology (JP)
  • Institute of Mathematics for Industry, Kyushu University (JP)
  • Chiba University (JP)
  • Kanazawa University (JP)
  • The University of Osaka (JP)
  • The Cancer Institute Hospital (JP)
  • National Center for Global Health and Medicine (JP)
  • National Institute of Genetics (JP)
  • Research Institute for Microbial Diseases, The University of Osaka (JP)
  • Japan Agency for Medical Research and Development (JP)
Corresponding author
Takahashi, Akiko
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2022-12-28
Volume
5
Issue
1
Pages
1420-1420
ISSN
2399-3642 (ISSN-L)
DOI
10.1038/s42003-022-04369-7
PMC
PMC9797495
OpenAlex
W4312224758
Cited by
23
References
17
Citations by year
2026: 4 · 2025: 5 · 2024: 8 · 2023: 6
FWCI
2.94
Type
journal article
Language
en
Update notices
correction (2025-12-30)
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Japan Agency for Medical Research and Development (19gm6110023h0001)
  • MEXT | JST | Precursory Research for Embryonic Science and Technology (JPMJPR17H7)
  • MEXT | Japan Science and Technology Agency (JPMJPS2022)
  • MEXT | Japan Society for the Promotion of Science (17K19618, 19H03507, 22H02907)
  • Naito Foundation
  • Uehara Memorial Foundation
  • Foundation for Promotion of Cancer Research
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords
RNASEH2A, cellular senescence, senescence-associated secretory phenotype, E2F transcription factors, Werner syndrome, colorectal cancer metastasis, aging, inflammatory gene expression
MeSH terms
Animals, Cell Line, DNA, Humans, Ligands, Neoplasms, Nucleotides, Phenotype, Down-Regulation, Gene Expression, Cellular Senescence, Genomics, Mice, DNA Fragmentation

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