Permanent cell cycle exit in G2 phase after DNA damage in normal human fibroblasts
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Although the Cdk inhibitor p21(Waf1/Cip1), one of the transcriptional targets of p53, has been implicated in the maintenance of G(2) arrest after DNA damage, its function at this stage of the cell cycle is not really understood. Here, we show that the exposure of normal human fibroblasts (NHFs) to genotoxic agents provokes permanent cell cycle exit in G(2) phase, whereas mouse embryo fibroblasts and transformed human cells progress through mitosis and arrest in G(1) without intervening cytokinesis. p21(Waf1/Cip1) exerts a key role in driving this G(2) exit both by inhibiting cyclin B1-Cdk1 and cyclin A-Cdk1/2 complexes, which control G(2)/M progression, and by blocking the phosphorylation of pRb family proteins. NHFs with compromised pRb proteins could still efficiently arrest in G(2) but were unable to exit the cell cycle, resulting in cell death. Our experiments show that, when under continuous genotoxic stress, normal cells can reverse their commitment to mitotic progression due to passage through the restriction point and that mechanisms involving p21(Waf1/Cip1) and pocket proteins can induce exit in G(2) and G(1).
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Cyclin B1-CDK1 complexes bound to p21 in the nucleus are inactive and cannot be activated upon CDK1 dephosphorylation by phosphatase CDC25C.
“In fact, cyclin B1–CDK1 complexes bound to p21 in the nucleus are inactive and cannot be activated upon CDK1 dephosphorylation by phosphatase CDC25C [60,61].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [60]
In primary fibroblasts exposed to genotoxic drugs, p21 associates with and sequesters inactive cyclin B1-Cdk1 complexes in the nucleus, preventing mitotic entry.
“In primary fibroblasts exposed to genotoxic drugs, in addition to inhibiting cyclin A-Cdk1/2 complexes, 59 p21 also associates with and sequesters inactive cyclin B1-Cdk1 complexes in the nucleus, thereby preventing mitotic entry 69 (Fig. 2).”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [59]
The G2 exit program was proposed to act as a safeguard preventing adaptation to the G2 checkpoint and passage of damaged cells into mitosis.
“Based on these findings, it was proposed that the “G2 exit program” might serve as a safeguard mechanism to prevent cell adaptation to the G2 checkpoint and consequently the passage into mitosis of cells with damaged DNA (Fig. 2; 59 ).”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [59]
Prolonged ICRF-193 exposure in normal human fibroblasts causes p53/p21-dependent irreversible G2 exit, with reduced cyclin A and B1 and accumulation of non-phosphorylated pRb family pocket proteins.
“Prolonged exposure to this drug led to p53/p21dependent irreversible cell cycle exit in G2 that was associated with down-regulation of both cyclin A and cyclin B1 and accumulation of non-phosphorylated pRb family pocket proteins.59”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [59]
Without prolonged Chk1/2 activation, cells lacking p53 and p21 that are exposed to DNA-damaging agents arrest in G2 only briefly.
“In the absence of sustained Chk1/2 activation, p53/p21-deficient cells exposed to genotoxic agents arrest only transiently in G2 and then progress into mitosis and eventually die.59,93”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [59]
These cells then progress into mitosis and eventually die.
“In the absence of sustained Chk1/2 activation, p53/p21-deficient cells exposed to genotoxic agents arrest only transiently in G2 and then progress into mitosis and eventually die.59,93”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [59]
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- Authors
- Baus, F., Gire, V., Fisher, D., Piette, J., & Dulić, V.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Dulić, Vjekoslav
- Venue
- The EMBO Journal
- Published
- 2003-08-01
- Volume
- 22
- Issue
- 15
- Pages
- 3992-4002
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC169060
- OpenAlex
- W2035568149
- Cited by
- 143
- References
- 39
- Citations by year
- 2025: 1 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 7 · 2020: 10 · 2019: 3 · 2018: 7 · 2017: 6 · 2016: 9 · 2015: 7 · 2014: 6 · 2013: 11 · 2012: 9
- FWCI
- 3.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Israel Cancer Research Fund
- Ligue Contre le Cancer
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- G2 phase, DNA damage, p21, p53, normal human fibroblasts, CDK1-cyclin B1, retinoblastoma protein phosphorylation, restriction point, genotoxic stress, cell death, G2/M transition, mitotic progression
- MeSH terms
- Bleomycin, Cells, Cultured, DNA Damage, Fibroblasts, Humans, Mitosis, Piperazines, G2 Phase, Cyclins, Cyclin-Dependent Kinases, Cyclin-Dependent Kinase Inhibitor p21, Diketopiperazines
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