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Cell fate decision mediated by p53 pulses
Open accessAbstract
The tumor suppressor p53 plays a crucial role in cellular response to various stresses. Recent experiments have shown that p53 level exhibits a series of pulses after DNA damage caused by ionizing radiation (IR). However, how the p53 pulses govern cell survival and death remains unclear. Here, we develop an integrated model with four modules for the p53 network and explore the mechanism for cell fate decision based on the dynamics of the network. By numerical simulations, the following processes are characterized. First, DNA repair proteins bind to IR-induced double-strand breaks, forming complexes, which are then detected by ataxia telangiectasia mutated (ATM). Activated ATM initiates the p53 oscillator to produce pulses. Consequently, the target genes of p53 are selectively induced to control cell fate. We propose that p53 promotes the repair of minor DNA damage but suppresses the repair of severe damage. We demonstrate that cell fate is determined by the number of p53 pulses relying on the extent of DNA damage. At low damage levels, few p53 pulses evoke cell cycle arrest by inducing p21 and promote cell survival, whereas at high damage levels, sustained p53 pulses trigger apoptosis by inducing p53AIP1. We find that p53 can effectively maintain genomic integrity by regulating the efficiency and fidelity of DNA repair. We also show that stochasticity in the generation and repair of DNA damage leads to variability in cell fate. These findings are consistent with experimental observations and advance our understanding of the dynamics and functions of the p53 network.
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“TP53 plays a central role in regulating cellular responses to genotoxic stress13–17”
From Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia (2015) · cites this paper as [16]
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Metadata
- Authors
- Zhang, X.-P., Liu, F., Cheng, Z., & Wang, W.
- Affiliations
- National Laboratory of Solid State Microstructures (CN)
- University of California San Diego (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-07-28
- Volume
- 106
- Issue
- 30
- Pages
- 12245-12250
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2710988
- OpenAlex
- W2068371312
- Cited by
- 253
- References
- 59
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 12 · 2023: 9 · 2022: 16 · 2021: 19 · 2020: 20 · 2019: 17 · 2018: 7 · 2017: 12 · 2016: 15 · 2015: 16 · 2014: 19 · 2013: 13 · 2012: 23
- FWCI
- 10.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (10834002)
- Program for New Century Excellent Talents in University (NCET-08, NCET-08-0269)
- National Key Research and Development Program of China (2006CB910302, 2007CB814806)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Keywords
- p53, p53 oscillations, cell fate determination, ionizing radiation, DNA damage response, ATM, DNA repair, DNA double-strand breaks, p21, p53AIP1, apoptosis, cell cycle arrest, genome stability, randomness
- MeSH terms
- Algorithms, Cell Survival, DNA Repair, DNA-Binding Proteins, Humans, Models, Biological, Protein Binding, Radiation, Ionizing, Signal Transduction, Tumor Suppressor Protein p53, Apoptosis, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Proto-Oncogene Proteins c-bcl-2, Tumor Suppressor Proteins, Cytochromes c, Proto-Oncogene Proteins c-mdm2, Caspase 3, DNA Breaks, Double-Stranded, Ataxia Telangiectasia Mutated Proteins
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