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A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity
Open accessAbstract
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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Mosteiro, L., Pantoja, C., de Martino, A., & Serrano, M. (2018) · Aging Cell · doi:10.1111/acel.12711 · Cited by 182
“The tumor suppressor genes p53, p21, Ink4a, and Arf act as cell-autonomous barriers for cellular reprogramming (Banito et al., 2009; Kawamura et al., 2009; Li et al., 2009; Marion et al., 2009; Utikal et al., 2009; Zhao et al., 2008).”
BackgroundSelf-citationZunder, E. R., Lujan, E., Goltsev, Y., Wernig, M., & Nolan, G. P. (2015) · Cell stem cell · doi:10.1016/j.stem.2015.01.015 · Cited by 180
“Total protein levels of the tumor suppressor protein p53, which has been shown to inhibit cellular reprogramming (Hong et al., 2009; Kawamura et al., 2009; Li et al., 2009; Marión et al., 2009; Utikal et al., 2009), increased rapidly after transgene induction, and phosphorylation levels of the ribosomal protein S6, a…”
BackgroundMolecular classification of prostate cancer using curated expression signatures
Markert, E. K., Mizuno, H., Vázquez, A., & Levine, A. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117029108 · Cited by 182
Mallanna, S. K., & Rizzino, A. (2010) · Developmental Biology · doi:10.1016/j.ydbio.2010.05.014 · Cited by 185
“the efficiency of generating iPS cells (Banito et al., 2009; Hong et al., 2009; Kawamura et al., 2009; Li et al., 2009; Marion et al., 2009).”
BackgroundKokkinaki, M., Sahibzada, N., & Golestaneh, N. (2011) · Stem Cells · doi:10.1002/stem.635 · Cited by 189
“Recently, the effect of viral reprogramming on induction of DNA damage and loss of DNA damage-induced G(1)/S cell cycle arrest in iPS cells has been reported [27].”
BackgroundMethodInduced Neuronal Cells: How to Make and Define a Neuron
Yang, N., Ng, Y. H., Pang, Z. P., Südhof, T. C., & Wernig, M. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.11.015 · Cited by 185
Direct Neuronal Reprogramming: Achievements, Hurdles, and New Roads to Success
Gascón, S., Masserdotti, G., Russo, G. L., & Götz, M. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.06.011 · Cited by 183
“For example, ablation of the p53-p21 pathway accelerates the kinetics of iPSC generation (Kawamura et al., 2009; Utikal et al., 2009) at the expense of a higher rate of chromosomal aberrations (Marión et al., 2009).”
BackgroundAging and reprogramming: a two-way street
Mahmoudi, S., & Brunet, A. (2012) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2012.10.004 · Cited by 171
iPS cells: A source of cardiac regeneration
Yoshida, Y., & Yamanaka, S. (2010) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2010.10.026 · Cited by 178
“The tumor suppressor protein p53 and cell-cycle regulator INK4A have been reported to act as a barrier to reprogramming of somatic cells to iPS cells, and the blockade of these genes also increases the reprogramming efficiency.[48-52] Some transcription factors, such as ESRRB and UTF1, have been found to enhance the r…”
BackgroundYoshida, Y., & Yamanaka, S. (2010) · Circulation · doi:10.1161/circulationaha.109.881433 · Cited by 176
“Social Life” of Senescent Cells: What Is SASP and Why Study It?
Borodkina, A. V., Deryabin, P. I., Giukova, А. А., & Nikolsky, N. N. (2018) · Acta Naturae · doi:10.32607/20758251-2018-10-1-4-14 · Cited by 170
Mesenchymal Stem Cell Senescence and Rejuvenation: Current Status and Challenges
Xueke, Z., Hong, Y., Zhang, H., & Li, X. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00364 · Cited by 170
“First reported in 2006, induced pluripotent stem cells (iPSCs) have been established as useful tools for regenerative medicine (Marion, 2009; Frobel, 2014).”
Backgroundp53 loss promotes acute myeloid leukemia by enabling aberrant self-renewalPreprint
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“…suppression of p53 or the p53 pathway enhances the production of induced pluripotent stem (iPS) cells, suggesting that p53 limits the reprogramming of differentiated cells into a self-renewing state (Hong et al. 2009; Kawamura et al. 2009; Li et al. 2009; Marion et al. 2009; Utikal et al. 2009).”
BackgroundDerivation of Induced Pluripotent Stem Cells from Human Peripheral Blood T Lymphocytes
Brown, M. E., Rondon, E., Rajesh, D., Mack, A. A., Lewis, R. L., Feng, X., Zitur, L. J., Learish, R. D., & Nuwaysir, E. F. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011373 · Cited by 167
“Experiments involving manipulation of anti-proliferative pathways [19,20,21,22] offer insights into the mechanisms of reprogramming and may significantly augment reprogramming efficiencies.”
BackgroundCurrent understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme
England, B., Huang, T., & Karsy, M. (2013) · Tumor Biology · doi:10.1007/s13277-013-0871-3 · Cited by 163
Role of shelterin in cancer and aging
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BackgroundSelf-citationThe Developmental Potential of iPSCs Is Greatly Influenced by Reprogramming Factor Selection
Buganim, Y., Markoulaki, S., van Wietmarschen, N., Hoke, H., Wu, T., Ganz, K., Akhtar-Zaidi, B., He, Y., Abraham, B. J., Porubsky, D., et al. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.07.003 · Cited by 163
“Consistent with Myc being a very potent oncogene (González et al., 2013; Marión et al., 2009; Müller et al., 2012), we observed a significant increase in γ-H2A.”
BackgroundGain-of-Function Mutant p53: All the Roads Lead to Tumorigenesis
Stein, Y., Rotter, V., & Aloni-Grinstein, R. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20246197 · Cited by 169
Patient-derived induced pluripotent stem cells in cancer research and precision oncology
Papapetrou, E. P. (2016) · Nature Medicine · doi:10.1038/nm.4238 · Cited by 163
Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures
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The Warburg effect version 2.0: Metabolic reprogramming of cancer stem cells
Menéndez, J. A., Joven, J., Cufí, S., Corominas-Faja, B., Oliveras‐Ferraros, C., Cuyàs, E., Martı́n-Castillo, B., López‐Bonet, E., Alarcón, T., & Vázquez‐Martín, A. (2013) · Cell Cycle · doi:10.4161/cc.24479 · Cited by 165
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“The data show how a molecular mechanism for sustaining th times in CNS development has been co-opted by high-grade gl tions in both normal andmalignant neural progenitor cells viam ings shed light on developmental origins of these tumors and relationship between p53, p21 and the stem cell phenotype (Hong et al., 2009;…”
BackgroundDeficiency of microRNA miR-34a expands cell fate potential in pluripotent stem cells
Choi, Y. J., Lin, C., Risso, D., Chen, S., Kim, T. A., Tan, M. H., Li, J. B., Wu, Y., Chen, C., Xuan, Z., et al. (2017) · Science · doi:10.1126/science.aag1927 · Cited by 158
Ubiquitin‐specific proteases 7 and 11 modulate Polycomb regulation of the INK4a tumour suppressor
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“EMBO open”
Backgroundp53 is balancing development, differentiation and de-differentiation to assure cancer prevention
Molchadsky, A., Rivlin, N., Brosh, R., Rotter, V., & Sarig, R. (2010) · Carcinogenesis · doi:10.1093/carcin/bgq101 · Cited by 161
Rejuvenating Strategies for Stem Cell-Based Therapies in Aging
Neves, J., Sousa‐Victor, P., & Jasper, H. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.01.008 · Cited by 160
“This perturbation, however, compromises genomic stability in the generated iPSCs, suggesting that p53 activation is a protective mechanism to ensure genomic integrity in the newly generated SCs (Marion et al., 2009a).”
Feeder-Free Derivation of Human Induced Pluripotent Stem Cells with Messenger RNA
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“The tumor suppressor p53, which plays a pivotal role in maintaining genome fidelity (Levine and Oren, 2009), was recently demonstrated to counteract somatic cell reprogramming (Zhao et al., 2008; Hong et al., 2009; Kawamura et al., 2009; Li et al., 2009; Marión et al., 2009; Utikal et al., 2009).”
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“cell senescence and markedly increases the efficiency of reprogramming (Hong et al., 2009; Kawamura et al., 2009; Li et al., 2009; Marión et al., 2009; Utikal et al., 2009).”
p27Kip1 Directly Represses Sox2 during Embryonic Stem Cell Differentiation
Li, H., Collado, M., Villasante, A., Matheu, A., Lynch, C. J., Cañamero, M., Rizzoti, K., Carneiro, C., Martínez, G., Vidal, A., et al. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.09.014 · Cited by 157
Self-citation
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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