Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response
Open accessAbstract
Telomeres cap the ends of chromosomes and regulate the replicative life span of human somatic cells. Telomere function is lost upon critical shortening and a p53-dependent checkpoint that detects altered telomere states at the G1/S transition was proposed to act as a regulator of the telomere damage response. We show that telomerase-negative human fibroblasts spend more time in G2 phase as they approach senescence and this delay is associated with manifestations of telomere dysfunction and the triggering of an ATM/ATR-dependent DNA damage signal. This correlates with a partial release of telomeric proteins TRF1 and TRF2. Analysis of the consequences of TRF1 and TRF2 depletion or over-expression of mutated versions revealed that telomere uncapping or telomere replication stress also led to DNA damage signalling in G2. Progression through mitosis of these cells was associated with signs of incomplete telomere terminal processing. We also observed an increase in sister chromatid-type telomere aberrations in senescing fibroblasts indicating that defects of telomere post-replicative events increased as cells age. Our results link a post-replicative damage response at eroded telomeres to G2 arrest signalling and challenge the current paradigm that the checkpoint response to short telomeres occurs primarily at the G1/S transition in human cells.
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Cellular senescence can also start during the G2 phase in response to telomere damage, DNA damage, or oncogene activation.
“Although traditionally described as an irreversible form of G1 arrest, cellular senescence can also start during the G2 phase in response to telomere damage [57], DNA damage [58], or oncogene activation [59].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [57]
Upon telomere erosion, senescing human fibroblasts show a prolonged G2 arrest, indicative of some mitotic entry delay.
“Upon telomere erosion, senescing human fibroblasts show a prolonged G2 arrest, indicative of some mitotic entry delay [57].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [57]
A clear loss of shelterin association with telomeres has been observed in senescent fibroblasts, which is consistent with the progressive displacement of these complexes from short telomeres.
“A clear loss of shelterin association with telomeres has been observed in senescent fibroblasts, which is consistent with the progressive displacement of these complexes from short telomeres [57].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [57]
The activation in senescing cells of G2/M phase checkpoint markers clearly indicates that their telomeres are somehow dysfunctional, most likely after telomere losses during DNA replication.
“The activation in senescing cells of G2/M phase checkpoint markers clearly indicates that their telomeres are somehow dysfunctional, most likely after telomere losses during DNA replication [57].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [57]
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 [57]
Acute loss of telomere end protection is unlikely to mimic the events leading to replicative senescence because in senescent cells, fusions between dysfunctional sister chromatids in end-to-end joining events are more frequent than inter-chromosomal end-to-end fusions.
“This acute loss of telomere end protection is unlikely to mimic the events leading to replicative senescence because in senescent cells, fusions between dysfunctional sister chromatids in end-to-end joining events are more frequent than inter-chromosomal end-to-end fusions (a consequence of complete exposure of the telomeric tract to the NHEJ pathway) [57].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [57]
The mean telomere length in human senescent fibroblasts ranges between 6 and 8 kbp, but senescent cells might contain a few extremely short telomeres that have lost completely their protective function and expose telomere-free ends, leading to DDR activation and cell cycle arrest.
“The mean telomere length in human senescent fibroblasts ranges between 6 and 8 kbp, but senescent cells might contain a few extremely short telomeres [94] that have lost completely their protective function and expose telomere-free ends, leading to DDR activation and cell cycle arrest [10,57].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [57]
Consequently, the cell cycle stalls in G2 to provide time for the re-establishment of the folded structure after replication.
“Consequently, the cell cycle stalls in G2 to provide time for the re-establishment of the folded structure after replication [57].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [57]
In telomerase-negative cells, eroded telomeres elicit a DNA damage response predominantly in G2, leading to p53/p21-dependent arrest or exit with 4N DNA content.
“More recently, it has been shown that in telomerase-negative cells eroded telomeres elicit DDR predominantly in G2, leading to p53/p21-dependent cell cycle arrest/ exit with 4N DNA content.81”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [81]
In aging cells, telomeric DNA damage persists at a subset of the shortest telomeres and fully activates the DNA damage response, unlike functional telomeres that trigger a transient protective response in G2.
“Unlike functional telomeres that trigger a transient DNA damage response in G2 that is required for their protection, 82 telomeric DNA damage in aging cells persists at a subset of the shortest telomeres and fully activates DDR.81”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [81]
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Mechanisms and Regulation of Cellular Senescence
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- Authors
- Jullien, L., Mestre, M., Roux, P., & Gire, V.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Gire, Véronique
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-11-26
- Volume
- 41
- Issue
- 2
- Pages
- 900-911
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC3553962
- OpenAlex
- W1978389188
- Cited by
- 32
- References
- 43
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 5 · 2020: 2 · 2019: 2 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 2 · 2013: 4
- FWCI
- 1.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Ligue Contre le Cancer
- Fondation de France
- 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
- telomere shortening, telomere uncapping, G2 checkpoint, telomere dysfunction, senescence, TRF1, TRF2
- MeSH terms
- Cells, Cultured, DNA Damage, DNA-Binding Proteins, Fibroblasts, Humans, Mitosis, Tumor Suppressor Protein p53, Retinoblastoma Protein, G2 Phase, Telomere, Cellular Senescence, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Telomeric Repeat Binding Protein 1, Telomeric Repeat Binding Protein 2, Telomere Shortening, G2 Phase Cell Cycle Checkpoints, Ataxia Telangiectasia Mutated Proteins
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