Abstract
The p53 protein has a highly evolutionarily conserved role in metazoans as ‘guardian of the genome’, mediating cell-cycle arrest and apoptosis in response to genotoxic injury1. In large, long-lived animals with substantial somatic regenerative capacity, such as vertebrates, p53 is an important tumour suppressor—an attribute thought to stem directly from its induction of death or arrest in mutant cells with damaged or unstable genomes. Chemotherapy and radiation exposure both induce widespread p53-dependent DNA damage. This triggers potentially lethal pathologies2 that are generally deemed an unfortunate but unavoidable consequence of the role p53 has in tumour suppression. Here we show, using a mouse model in which p53 status can be reversibly switched in vivo between functional and inactive states3, that the p53-mediated pathological response to whole-body irradiation, a prototypical genotoxic carcinogen, is irrelevant for suppression of radiation-induced lymphoma. In contrast, delaying the restoration of p53 function until the acute radiation response has subsided abrogates all of the radiation-induced pathology yet preserves much of the protection from lymphoma. Such protection is absolutely dependent on p19ARF—a tumour suppressor induced not by DNA damage, but by oncogenic disruption of the cell cycle.
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Acknowledgements
We thank F. Rostker and the Genome and Pathology Cores at UCSF for technical assistance, J. Hwang for statistical analysis, J. H. Mao, F. McCormick, C. O'Shea, K. Shannon and the entire Evan laboratory for critical discussions. We thank T. Littlewood and D. Martin Zanca for showing that the p53ERTAM knockin mouse was feasible. This work was supported by grants from the National Cancer Institute and National Institute on Aging.
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Supplementary Notes
This file contains a detailed description of the Supplementary Methods. (PDF 76 kb)
Supplementary Figure Legends
This file contains text to accompany the below Supplementary Figures. (PDF 77 kb)
Supplementary Figure 1
Global DNA damage is rapidly resolved in p53KI/KI tissues after a single acute dose of y-irradiation (PDF 6483 kb)
Supplementary Figure 2
The p53-dependent response to acute DNA damage decays rapidly in p53+/+ tissues after a single acute dose of y-irradiation (PDF 7138 kb)
Supplementary Figure 3
p53 restoration in p53KI/KI animals delays the development of spontaneous lymphoma (PDF 35 kb)
Supplementary Figure 4
p19ARF protein is expressed in lymphoid tumors arising in p53KI/KI mice never exposed to 4-OHT (PDF 149 kb)
Supplementary Figure 5
Schematic representation of the proposed roles of p53 in acute DNA damage responses and tumor suppression (PDF 38 kb)
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Christophorou, M., Ringshausen, I., Finch, A. et al. The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443, 214–217 (2006). https://doi.org/10.1038/nature05077
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DOI: https://doi.org/10.1038/nature05077
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