DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts.

Di Leonardo, A; Linke, S P; Clarkin, K; Wahl, G M

doi:10.1101/gad.8.21.2540

Cited by 1,215Cancer-related Molecular PathwaysDNA Repair MechanismsTelomeres, Telomerase, and Senescence

DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts.

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Di Leonardo, A, Linke, S P, Clarkin, K, Wahl, G M·1994·Genes & Development

DOI 10.1101/gad.8.21.2540

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Abstract

The tumor suppressor p53 is a cell cycle checkpoint protein that contributes to the preservation of genetic stability by mediating either a G1 arrest or apoptosis in response to DNA damage. Recent reports suggest that p53 causes growth arrest through transcriptional activation of the cyclin-dependent kinase (Cdk)-inhibitor Cip1. Here, we characterize the p53-dependent G1 arrest in several normal human diploid fibroblast (NDF) strains and p53-deficient cell lines treated with 0.1-6 Gy gamma radiation. DNA damage and cell cycle progression analyses showed that NDF entered a prolonged arrest state resembling senescence, even at low doses of radiation. This contrasts with the view that p53 ensures genetic stability by inducing a transient arrest to enable repair of DNA damage, as reported for some myeloid leukemia lines. Gamma radiation administered in early to mid-, but not late, G1 induced the arrest, suggesting that the p53 checkpoint is only active in G1 until cells commit to enter S phase at the G1 restriction point. A log-linear plot of the fraction of irradiated G0 cells able to enter S phase as a function of dose is consistent with single-hit kinetics. Cytogenetic analyses combined with radiation dosage data indicate that only one or a small number of unrepaired DNA breaks may be sufficient to cause arrest. The arrest also correlated with long-term elevations of p53 protein, Cip1 mRNA, and Cip1 protein. We propose that p53 helps maintain genetic stability in NDF by mediating a permanent cell cycle arrest through long-term induction of Cip1 when low amounts of unrepaired DNA damage are present in G1 before the restriction point.

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Oxidative stress has been ensured as a crucial factor for cellular senescence through shortening telomere and causing DNA double-strand breaks.
“Oxidative stress has been ensured as a crucial factor for cellular senescence through shortening telomere and causing DNA double-strand breaks.209,210”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [210]
The Discussion (page not specified) proposes that shortening telomeres may lead to double-strand breaks and activate an arrest pathway involved in senescence. It does not identify oxidative stress as the cause of telomere shortening or those breaks, and presents the senescence mechanism as speculation rather than established fact. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Many kinds of oncogenic or stressful stimuli can induce a senescence response, foremost certain types of DNA damage including DNA breaks and oxidative lesions.
“It is now apparent that many kinds of oncogenic or stressful stimuli can induce a senescence response. Foremost among these are certain types of DNA damage, including DNA breaks and oxidative lesions caused by environmental insults, genetic defects, or endogenous processes (DiLeonardo et al., 1994; Hasty et al., 2003; Samper et al., 2003).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as DiLeonardo et al., 1994
The Abstract and Discussion report that gamma irradiation caused prolonged arrest in normal human fibroblasts, with features characteristic of senescence; the Discussion says this suggests premature senescence. The paper supports DNA damage as one possible trigger, but does not establish the broader claims about oncogenic stimuli, oxidative lesions, or the listed sources of damage. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Senescence occurs in G1 and possibly G2 phase of the cell cycle, whereas quiescence happens in G0.
“Cellular senescence is different from another form of growth arrest known as quiescence, in that senescence occurs in G1 and possibly G2 phase of the cell cycle (Di Leonardo et al., 1994) as opposed to quiescence which happens in G0.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Di Leonardo et al., 1994
A single unresolved DNA DSB is capable of inducing senescence.
“It has been observed that a single unresolved DNA DSB is capable of inducing senescence (Di Leonardo et al., 1994).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Di Leonardo et al., 1994
Senescence-associated growth arrest depends functionally on the tumor-suppressor pathways controlled by p16INK4a and pRB, as well as by p53.
“senescence-associated growth arrest has been shown to depend functionally on the tumor- suppressor pathways controlled by p16INK4a and pRB (retinoblastoma protein), as well as by p53”
From Redox control of senescence and age-related disease. (2017) · cites this paper as [39]

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Authors: Di Leonardo, A., Linke, S. P., Clarkin, K., & Wahl, G. M.
Affiliations: Salk Institute for Biological Studies (US)
ORCID: Linke, S P
Wahl, G M
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 1994-11-01
Volume: 8
Issue: 21
Pages: 2540-2551
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.8.21.2540
OpenAlex: W2028361915
Cited by: 1,215
References: 82
Citations by year: 2026: 21 · 2025: 25 · 2024: 26 · 2023: 39 · 2022: 32 · 2021: 27 · 2020: 36 · 2019: 32 · 2018: 20 · 2017: 30 · 2016: 38 · 2015: 36 · 2014: 41 · 2013: 37 · 2012: 33
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Energy
Associazione Italiana per la Ricerca sul Cancro
Fondazione Italiana per la Ricerca sul Cancro
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords: p53, G1 cell cycle arrest, DNA damage, gamma radiation, cellular senescence, genetic stability, single-hit kinetics, cell cycle checkpoints, cyclin-dependent kinase inhibitors, p53-deficient cells
MeSH terms: Cell Cycle, Cell Line, Chromosome Aberrations, DNA Damage, Dose-Response Relationship, Radiation, Fibroblasts, Flow Cytometry, Gamma Rays, Humans, Kinetics, Leukemia, Myeloid, Metaphase, RNA, Messenger, Skin, Time Factors, Blotting, Northern, Blotting, Western, Tumor Suppressor Protein p53, G1 Phase, Cyclins, Protein Kinase Inhibitors, Cyclin-Dependent Kinase Inhibitor p21

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DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts.

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