DNA damage-induced cellular senescence is sufficient to suppress tumorigenesis: a mouse model
Open accessAbstract
Tumor suppressor p53-dependent apoptosis is critical in suppressing tumorigenesis. Previously, we reported that DNA double-strand breaks (DSBs) at the V(D)J recombination loci induced genomic instability in the developing lymphocytes of nonhomologous end-joining (NHEJ)–deficient, p53-deficient mice, which led to rapid lymphomagenesis. To test the ability of p53-dependent cell cycle arrest to suppress tumorigenesis in the absence of apoptosis in vivo, we crossbred NHEJ-deficient mice into a mutant p53R172P background; these mice have defects in apoptosis induction, but not cell cycle arrest. These double-mutant mice survived longer than NHEJ/p53 double-null mice and, remarkably, were completely tumor free. We detected accumulation of aberrant V(D)J recombination–related DSBs at the T cell receptor (TCR) locus, and high expression levels of both mutant p53 and cell cycle checkpoint protein p21, but not the apoptotic protein p53-upregulated modulator of apoptosis. In addition, a substantial number of senescent cells were observed among both thymocytes and bone marrow cells. Cytogenetic studies revealed euploidy and limited chromosomal breaks in these lymphoid cells. The results indicate that precursor lymphocytes, which normally possess a high proliferation potential, are able to withdraw from the cell cycle and undergo senescence in response to the persistence of DSBs in a p53–p21–dependent pathway; this is sufficient to inhibit oncogenic chromosomal abnormality and suppress tumorigenesis.
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Tumor cells activate the PKA-CREB and P38 pathways by producing cAMP, thereby causing DNA damage and senescence of T cells.
“In addition, tumor cells activate the PKA-CREB and P38 pathways by producing cAMP, thereby causing DNA damage and senescence of T cells [51, 53, 58–63].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [61]
DNA damage can cause mouse thymic precursor lymphocytes to withdraw from the cell cycle and undergo senescence.
“DNA damage can cause mouse thymic precursor lymphocytes to withdraw from the cell cycle and undergo senescence [59].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [59]
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- Authors
- Van Nguyen, T., Puebla-Osorio, N., Pang, H., Dujka, M. E., & Zhu, C.
- Affiliations
- 1Department of Immunology, the University of Texas M.D. Anderson Cancer Center,
- The University of Texas MD Anderson Cancer Center (US)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2007-05-29
- Volume
- 204
- Issue
- 6
- Pages
- 1453-1461
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2118600
- OpenAlex
- W2115000373
- Cited by
- 72
- References
- 55
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 1 · 2015: 5 · 2014: 3 · 2013: 5 · 2012: 5
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- cellular senescence, DNA double-strand breaks, p53, p21, V(D)J recombination, lymphomagenesis, genomic instability, cell cycle arrest, tumor suppression, thymocytes, chromosomal breaks, euploidy
- MeSH terms
- DNA Ligase ATP, Animals, Crosses, Genetic, Disease Models, Animal, Immunohistochemistry, Mice, Inbred C57BL, Mutation, Neoplasms, DNA Ligases, Blotting, Western, Tumor Suppressor Protein p53, Cellular Senescence, In Situ Hybridization, Fluorescence, In Situ Nick-End Labeling, Cytogenetic Analysis, Mice, DNA Breaks, Double-Stranded
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