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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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“Key tumor suppressors such as p53, p16 INK4a , or p21 CIP1 control the senescence response to OSKM, and their inhibition increases reprogramming (Banito et al. 2009; Hong et al. 2009; Kawamura et al. 2009; Li et al. 2009; Marion et al. 2009; Utikal et al. 2009).”
Park, S. J., Yeo, H. C., Kang, N., Kim, H., Lin, J., Ha, H., Vendrell, M., Lee, J., Chandran, Y., Lee, D., et al. (2014) · Stem Cell Research · doi:10.1016/j.scr.2014.03.002 · Cited by 65
“This include the activation of Cdkn1a, Cdkn2a, Trp53 identified in earlier studies (Kawamura et al., 2009; Marion et al., 2009; Mikkelsen et al., 2008; Utikal et al., 2009), and in addition, we found Scotin, Thbs1, Fas and Gadd45b/g to be similarly up-regulated.”
Turinetto, V., Orlando, L., & Giachino, C. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18091952 · Cited by 71
“Consequently, in the absence of p53, reprogramming efficiency increases significantly, but the generated iPSCs have a high risk of carrying genetic aberrations [28,94].”
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Biomarkers of Cancer Stem Cells for Experimental Research and Clinical Application
Saito, S., Ku, C., Wuputra, K., Pan, J.-B., Lin, C., Lin, Y., Wu, D., & Yokoyama, K. K. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12050715 · Cited by 66
A Cyclic AMP Analog, 8-Br-cAMP, Enhances the Induction of Pluripotency in Human Fibroblast Cells
Wang, Y., & Adjaye, J. (2010) · Stem Cell Reviews and Reports · doi:10.1007/s12015-010-9209-3 · Cited by 62
Walia, B., Satija, N. K., Tripathi, R. P., & Gangenahalli, G. U. (2011) · Stem Cell Reviews and Reports · doi:10.1007/s12015-011-9279-x · Cited by 62
Embryonic Stem Cells or Induced Pluripotent Stem Cells? A DNA Integrity Perspective
Baï, Q., Desprat, R., Klein, B., Lemaı̂tre, J.-M., & Vos, J. D. (2013) · Current Gene Therapy · doi:10.2174/1566523211313020003 · Cited by 68
Ojo, D., Lin, X., Wong, N., Gu, Y. J., & Tang, D. (2015) · Cancers · doi:10.3390/cancers7040890 · Cited by 64
“The p53 pathway inhibited the reprogramming [133–136]; and inactivation of p53 empowered SOX2-involved reprogramming of fibroblasts [133].”
BackgroundInduced pluripotent stem cells in Parkinson's disease: scientific and clinical challenges
Xiao, B., Ng, H., Takahashi, R., & Tan, E.-K. (2016) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2015-312036 · Cited by 69
SOX17 in cellular reprogramming and cancer
Tan, D. S., Holzner, M., Weng, M., Srivastava, Y., & Jauch, R. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.08.008 · Cited by 67
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Nicotinamide Overcomes Pluripotency Deficits and Reprogramming Barriers
Son, M. J., Son, M., Seol, B., Kim, M., Yoo, C. H., Han, M., & Cho, Y. S. (2013) · Stem Cells · doi:10.1002/stem.1368 · Cited by 64
Telomere rejuvenation during nuclear reprogramming
Marión, R. M., & Blasco, M. A. (2010) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2010.01.005 · Cited by 62
Self-citationCufí, S., Vázquez‐Martín, A., Oliveras‐Ferraros, C., Quirantes‐Piné, R., Segura‐Carretero, A., Micol, V., Joven, J., Bosch‐Barrera, J., Barco, S. D., Martı́n-Castillo, B., et al. (2012) · Cell Cycle · doi:10.4161/cc.11.6.19665 · Cited by 62
Induced pluripotent stem cells: what lies beyond the paradigm shift
Cox, J. L., & Rizzino, A. (2010) · Experimental Biology and Medicine · doi:10.1258/ebm.2009.009267 · Cited by 62
The p53–PUMA axis suppresses iPSC generation
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“P53 has been reported to be a critical barrier during somatic cell reprogramming (Marion et al., 2009) and also an important tumor suppressor (Levine and Oren, 2009).”
BackgroundAnesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway
Ni, C., Li, C., Dong, Y., Guo, X., Zhang, Y., & Xie, Z. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-9937-8 · Cited by 61
“DNA damage can trigger activation of p53 [[57, 58], reviewed in [59, 60]].”
Jiang, Y., Liu, F., Zou, F., Zhang, Y., Wang, B., Zhang, Y., Lian, A., Han, X., Liu, Z., Liu, X., et al. (2019) · Stem Cell Research & Therapy · doi:10.1186/s13287-019-1382-y · Cited by 60
Biswal, B. K., Beyrouthy, M. J., Hever-Jardine, M. P., Armstrong, D., Tomlinson, C. R., Christensen, B. C., Marsit, C. J., & Spinella, M. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0053003 · Cited by 63
“Notably, recent evidence suggests that p53 is a barrier for induced pluripotency of somatic cells and has antistemness and prodifferentiation functions in ES and EC cells [37–40].”
BackgroundProgress and Promise Towards Safe Induced Pluripotent Stem Cells for Therapy
Seifinejad, A., Tabebordbar, M., Baharvand, H., Boyer, L. A., & Salekdeh, G. H. (2010) · Stem Cell Reviews and Reports · doi:10.1007/s12015-010-9121-x · Cited by 59
“Recently, several groups showed that the inactivation of P53 remarkably increased the efficiency of iPSCs generation [86–90].”
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Human induced pluripotent stem cells—from mechanisms to clinical applications
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TRIM28 Is an Epigenetic Barrier to Induced Pluripotent Stem Cell Reprogramming
Miles, D. C., de Vries, N. A., Gisler, S., Lieftink, C., Akhtar, W., Gogola, E., Pawlitzky, I., Hulsman, D., Tanger, E., Koppens, M. A. J., et al. (2016) · Stem Cells · doi:10.1002/stem.2453 · Cited by 60
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“[5,6,7,8,9], although without a clear consensus on mechanisms by”
BackgroundProtein intrinsic disorder and induced pluripotent stem cells
Xue, B., Oldfield, C. J., Van, Y.-Y. J., Dunker, A. K., & Uversky, V. N. (2011) · Molecular BioSystems · doi:10.1039/c1mb05163f · Cited by 60
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The dual role of p53: DNA protection and antioxidant
Borrás, C., Gómez‐Cabrera, M. C., & Viña, J. (2011) · Free Radical Research · doi:10.3109/10715762.2011.571685 · Cited by 58
“In fact, many kinds of DNA damage such as hypoxia [6], spindle poisons [7], telomere shortening [8], heat and cold shock [9,10], nutrient defi ciency [11] and the mutational activation of some oncogenes [12 – 14]”
BackgroundGene-delivery systems for iPS cell generation
Shao, L., & Wu, W.-S. (2010) · Expert Opinion on Biological Therapy · doi:10.1517/14712590903455989 · Cited by 63
“In addition, recent studies demonstrated that the Ink4/Arf and p53-p21 pathway serve a barrier in iPS cell generation [76-81].”
BackgroundOne billion years of p53/p63/p73 evolution
Белый, В. А., & Levine, A. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910634106 · Cited by 58
Genomic instability in iPS: time for a break
Blasco, M. A., Serrano, M., & Fernández-Capetillo, Ó. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.50 · Cited by 59
“In fact, a previous report had already shown that cells undergoing reprogramming presented a pannuclear phosphorylation pattern of histone H2AX, which is reminiscent of RS (Marion et al, 2009).”
BackgroundSelf-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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