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A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity
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The reprogramming of differentiated cells to pluripotent cells (induced pluripotent stem (iPS) cells) is known to be an inefficient process. We recently reported that cells with short telomeres cannot be reprogrammed to iPS cells despite their normal proliferation rates, probably reflecting the existence of 'reprogramming barriers' that abort the reprogramming of cells with uncapped telomeres. Here we show that p53 (also known as Trp53 in mice and TP53 in humans) is critically involved in preventing the reprogramming of cells carrying various types of DNA damage, including short telomeres, DNA repair deficiencies, or exogenously inflicted DNA damage. Reprogramming in the presence of pre-existing, but tolerated, DNA damage is aborted by the activation of a DNA damage response and p53-dependent apoptosis. Abrogation of p53 allows efficient reprogramming in the face of DNA damage and the generation of iPS cells carrying persistent DNA damage and chromosomal aberrations. These observations indicate that during reprogramming cells increase their intolerance to different types of DNA damage and that p53 is critical in preventing the generation of human and mouse pluripotent cells from suboptimal parental cells.
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“In agreement with the negative role of prolonged p53 expression on stem cell potency, it was shown that p53 restricted the stem cell gene expression program [69].”
From Ultraviolet Radiation‐Induced Skin Aging: The Role of DNA Damage and Oxidative Stress in Epidermal Stem Cell Damage Mediated Skin Aging (2016) · cites this paper as [69]
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“…of direct reprogramming comparably to c-Myc in both mice and human (Banito et al. 2009; Hong et al. 2009; Kawam- ura et al. 2009; Li et al. 2009b; Marión et al. 2009; Uti- kal et al. 2009b). p53 induces differentiation in mouse ES cells, by suppression of Nanog expression (Lin et al. 2005).”
BackgroundMetabostemness in cancer: Linking metaboloepigenetics and mitophagy in remodeling cancer stem cells
Naik, P. P., Panigrahi, S., Parida, R., Praharaj, P. P., Bhol, C. S., Patil, S., Manjunath, N., Ghosh, D., Patra, S. K., & Bhutia, S. K. (2021) · Stem Cell Reviews and Reports · doi:10.1007/s12015-021-10216-9 · Cited by 20
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Telomere Biology in Stem Cells and Reprogramming
Batista, L. F. Z. (2014) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-397898-1.00003-7 · Cited by 22
Signals that regulate the oncogenic fate of neural stem cells and progenitors
Swartling, F. J., Bolin, S., Phillips, J. J., & Persson, A. I. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2013.01.027 · Cited by 22
Genome integrity: linking pluripotency and tumorgenicity
Deng, W., & Xu, Y. (2009) · Trends in Genetics · doi:10.1016/j.tig.2009.09.004 · Cited by 20
The p53-inducible CLDN7 regulates colorectal tumorigenesis and has prognostic significance
Hou, Y., Hou, L., Liang, Y., Zhang, Q., Hong, X., Wang, Y., Huang, X., Zhong, T., Pang, W., Xu, C., et al. (2020) · Neoplasia · doi:10.1016/j.neo.2020.09.001 · Cited by 21
“1, is a critical tumor suppressor involved in maintaining genomic integrity [3].”
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“While disarming of the p53 guardian mechanism does allow more stem cells to survive with a defective genome, it also exposes them to higher risks of tumorigenicity [235].”
Wang, Y., Lü, T., Sun, G., Zheng, Y., Yang, S., Zhang, H., Hao, S., Liu, Y., Ma, S., Zhang, H., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13411-y · Cited by 20
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“Five recent publications in Nature have shown that suppression of the p53 pathway leads to a marked improvement in the efficiency and kinetics of human and mouse cell reprogramming (Hong et al., 2009; Kawamura et al., 2009; Li et al., 2009a; Marion et al., 2009; Utikal et al., 2009).”
BackgroundInduced Pluripotent Stem Cells Are Sensitive to DNA Damage
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“However, it also raises the possibility of DNA damage and genomic instability accompanying the reprogramming process [18].”
BackgroundEpigenetic Regulation of Telomere Chromatin Integrity in Pluripotent Embryonic Stem Cells
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“One well-characterized means of enhancing reprogramming is to inhibit the activity of TP53/TRP53 (hereafter, p53) (Hong et al., 2009;Kawamura et al., 2009;Marion et al., 2009; Utikal et al., 2009).”
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“Importantly , during reprogramming, some of the cells enter the apoptosis (Marion et al. 2009a; Kawamura et al. 2009) or the senescence (Banito et al. 2009) pathways, which hampers iPSC generation and accounts, at least in part, for the low reprogramming efficiency.”
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“TP53 deletion or knockdown enhances the ability of differentiated cells to revert back to a pluripotent state (21, 22).”
Background
Metadata
- Authors
- Marión, R. M., Strati, K., Li, H., Murga, M., Blanco, R., Ortega, S., Fernandez-Capetillo, O., Serrano, M., & Blasco, M. A.
- Affiliations
- Spanish National Cancer Research Centre (ES)
- Venue
- Nature
- Published
- 2009-08
- Volume
- 460
- Issue
- 7259
- Pages
- 1149-1153
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3624089
- OpenAlex
- W2111920812
- Cited by
- 1,028
- References
- 29
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 13 · 2023: 20 · 2022: 37 · 2021: 24 · 2020: 35 · 2019: 45 · 2018: 46 · 2017: 51 · 2016: 60 · 2015: 72 · 2014: 84 · 2013: 110 · 2012: 135
- FWCI
- 53.60
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Ministerio de Ciencia e Innovación
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- p53, DNA damage response, induced pluripotent stem cells, cellular reprogramming, short telomeres, DNA repair deficiency, chromosomal abnormalities, genome stability, apoptosis, pluripotency
- MeSH terms
- Animals, Cells, Cultured, Chromosome Aberrations, DNA Damage, DNA Repair, Female, Fibroblasts, Humans, Male, Tumor Suppressor Protein p53, Telomere, Apoptosis, Pluripotent Stem Cells, Genomic Instability, Mice, Cellular Reprogramming
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