DNA damage checkpoint kinase Chk2 triggers replicative senescence
Open accessAbstract
Telomere shortening in normal human cells causes replicative senescence, a p53-dependent growth arrest state, which is thought to represent an innate defence against tumour progression. However, although it has been postulated that critical telomere loss generates a 'DNA damage' signal, the signalling pathway(s) that alerts cells to short dysfunctional telomeres remains only partially defined. We show that senescence in human fibroblasts is associated with focal accumulation of gamma-H2AX and phosphorylation of Chk2, known mediators of the ataxia-telangiectasia mutated regulated signalling pathway activated by DNA double-strand breaks. Both these responses increased in cells grown beyond senescence through inactivation of p53 and pRb, indicating that they are driven by continued cell division and not a consequence of senescence. gamma-H2AX (though not Chk2) was shown to associate directly with telomeric DNA. Furthermore, inactivation of Chk2 in human fibroblasts led to a fall in p21(waf1) expression and an extension of proliferative lifespan, consistent with failure to activate p53. Thus, Chk2 forms an essential component of a common pathway signalling cell cycle arrest in response to both telomere erosion and DNA damage.
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Replicative senescence is induced after serial propagation of normal human cells in culture and is caused by telomere erosion and the consequent increase in DNA lesions.
“It is induced after serial propagation of normal human cells in culture and is caused by telomere erosion and the consequent increase in DNA lesions [9,10,11,12].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [11]
In senescent cells, p53 transcriptional activity is increased through DNA damage response-dependent signals mainly driven by unresolved DNA damage signaling due to telomere erosion and oncogene hyperproliferation.
“In senescent cells, p53 transcriptional activity is increased through DNA damage response (DDR)-dependent signals mainly driven by unresolved DNA damage signaling due to telomere erosion and oncogene hyperproliferation [10,11,69,70,71].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [11]
In senescent human cells, short telomeres do not recapitulate the intermediate state phenotype predicted by the model of an ATM-activated but NHEJ-repressed state.
“However, in senescent human cells, short telomeres do not recapitulate the intermediate state phenotype predicted by this model (i.e., mild ATM activation without evidence of significant CHK2 and p53 activation) [10,11,12,57].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [11]
γH2AX focus formation correlates with the activation of the DNA damage effector kinases ATM, CHK1, and CHK2.
“γH2AX focus formation correlates with the activation of the DNA damage effector kinases ATM, CHK1, and CHK2 [10,11,12].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [11]
Foci of phosphorylated histone H2AX (γH2AX), which mark the presence of DNA breaks, accumulate at telomeres in human senescent fibroblasts.
“In this situation, foci of phosphorylated histone H2AX (γH2AX), which mark the presence of DNA breaks, accumulate at telomeres in human senescent fibroblasts [10,11,12].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [11]
Continuous DNA damage signaling is essential for maintenance of cell cycle arrest in senescence because inactivation of checkpoint kinases ATM, CHK2, and p53 results in escape from arrest.
“Continuous DNA damage signaling is essential for cell cycle arrest maintenance because inactivation of checkpoint kinases, such as ATM [10,12], CHK2 [11], and p53 [47,48], results in escape from this arrest.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [11]
Activated ATM/ATR phosphorylate CHK1 and CHK2, which phosphorylate p53; p53 phosphorylation displaces MDM2, liberating p53 from degradation and stimulating p21; p21 inhibits cell cycle progression by inhibiting cyclin-dependent kinases that phosphorylate and inactivate RB.
“Once activated, these kinases phosphorylate downstream factors including CHK1 and CHK2 that in turn phosphorylates p5329. Phosphorylation of p53 results in the displacement of the murine double minute 2 (MDM2) protein, liberating p53 from degradation and stimulation of the expression of the cyclin-dependent kinase inhibitor p21. p21 inhibits cell cycle progression by inhibiting cyclin-dependent”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [29]
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Self-citation
- Authors
- Gire, V., Roux, P., Wynford‐Thomas, D., Brondello, J., & Dulic, V.
- Affiliations
- Centre de Recherche en Biologie cellulaire de Montpellier (FR)
- Cardiff University (GB)
- Institut de Génétique Humaine (FR)
- Corresponding author
- Gire, Véronique
- Venue
- The EMBO Journal
- Published
- 2004-06-10
- Volume
- 23
- Issue
- 13
- Pages
- 2554-2563
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC449769
- OpenAlex
- W2088512897
- Cited by
- 198
- References
- 16
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 5 · 2023: 4 · 2022: 4 · 2021: 9 · 2020: 6 · 2019: 7 · 2018: 9 · 2017: 10 · 2016: 6 · 2015: 5 · 2014: 12 · 2013: 10 · 2012: 14
- FWCI
- 7.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- Chk2, replicative senescence, telomere shortening, DNA damage checkpoint, γH2AX, ataxia telangiectasia, p53 inactivation, retinoblastoma protein, p21, cell cycle arrest, telomeric DNA, human fibroblasts, DNA double-strand breaks
- MeSH terms
- Cell Cycle, Cell Line, DNA, DNA Damage, DNA Replication, Fibroblasts, Fluorescent Dyes, Histones, Humans, Lung, Male, Models, Biological, Phosphorylation, Retroviridae, Xanthenes, Blotting, Western, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, Retinoblastoma Protein, Telomere, Cellular Senescence, Protein Serine-Threonine Kinases, Microscopy, Confocal, Cell Cycle Proteins, Fluorescent Antibody Technique, Indirect, Telomerase, RNA, Small Interfering, Chromatin Immunoprecipitation, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Checkpoint Kinase 2
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