Cited by 1,028Pluripotent Stem Cells ResearchTelomeres, Telomerase, and SenescenceDNA Repair Mechanisms

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A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity

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Marión, Rosa M., Strati, Katerina, Li, Han, Murga, Matilde, Blanco, Raquel, Ortega, Sagrario, Fernandez-Capetillo, Oscar, Serrano, Manuel, Blasco, Maria A.·2009·Nature

DOI 10.1038/nature08287PMC PMC3624089

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Abstract

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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Stem cells for the treatment of neurodegenerative diseases
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Telomerase Protects Werner Syndrome Lineage-Specific Stem Cells from Premature Aging
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“Genomic instability due to p53 depletion in iPSCs has been previously reported (Kawamura et al., 2009; Marión et al., 2009a).”
Background
The paradigm of mutant p53-expressing cancer stem cells and drug resistance
Shetzer, Y., Solomon, H., Koifman, G., Molchadsky, A., Horesh, S., & Rotter, V. (2014) · Carcinogenesis · doi:10.1093/carcin/bgu073 · Cited by 105
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“…to pluripotency (Zhao et al , 2008; Banito et al , 2009; Hong et al , 2009; Kawamura et al , 2009; Krizhanovsky and Lowe, 2009; Li et al , 2009; Marion et al , 2009; Utikal et al , 2009), the efﬁciency of the oncogene-induced tumoural reprogramming of normal HS/P-Cs to terminally…”
Concise Review: Oct4 and More: The Reprogramming Expressway
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Positive feedback between p53 and TRF2 during telomere-damage signalling and cellular senescence
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Resveratrol Impedes the Stemness, Epithelial-Mesenchymal Transition, and Metabolic Reprogramming of Cancer Stem Cells in Nasopharyngeal Carcinoma through p53 Activation
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“Several studies indicated that p53 pathway decreases the efficiency of reprogramming of somatic cells to iPSCs [35–39].”
Background
Activation of Pluripotency Genes in Human Fibroblast Cells by a Novel mRNA Based Approach
Plews, J. R., Li, J., Jones, M., Moore, H. D. M., Mason, C., Andrews, P. W., & Na, J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0014397 · Cited by 104
“Induction of pluripotency in somatic cells needs to overcome the barrier imposed by DNA damage repair machinery [19,20,21,22,23,24,25].”
Δ40p53 controls the switch from pluripotency to differentiation by regulating IGF signaling in ESCsPreprint
Ungewitter, E. K., & Scrable, H. J. (2010) · Genes & Development · doi:10.1101/gad.1987810 · Cited by 101
“Depleting p53 levels by either shRNA or homologous recombination significantly increased the reprogramming efficiency of mouse embryonic fibroblasts (MEFs) (Hong et al. 2009; Kawamura et al. 2009; Li et al. 2009; Marion et al. 2009) and even enabled the reprogramming of cell types that normally are unable to generate…”
Background
Perspectives on cancer stem cells in osteosarcoma
Basu-Roy, U., Basilico, C., & Mansukhani, A. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.05.028 · Cited by 105
“Interestingly, the barrier that the p53 pathway poses to tumorigenesis, is also becoming evident from studies in induced pluripotent cells, where p53 blocks reprogramming of somatic cells to pluripotent cells [19; 20].”
Background
MiR‐138 Promotes Induced Pluripotent Stem Cell Generation Through the Regulation of the p53 Signaling
Ye, D., Wang, G., Liu, Y., Huang, W., Wu, M., Zhu, S., Jia, W., Deng, A., Liu, H., & Kang, J. (2012) · Stem Cells · doi:10.1002/stem.1149 · Cited by 99
Induced pluripotent stem cells and reprogramming: seeing the science through the hype
Belmonte, J. C. I., Ellis, J., Hochedlinger, K., & Yamanaka, S. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2700 · Cited by 98
Activation of AMP-activated protein kinase (AMPK) provides a metabolic barrier to reprogramming somatic cells into stem cells
Vázquez‐Martín, A., Vellón, L., Quirós, P. M., Cufí, S., de Galarreta, E. R., Oliveras‐Ferraros, C., Martín, Á. G., Martı́n-Castillo, B., López-Otı́n, C., & Menéndez, J. A. (2012) · Cell Cycle · doi:10.4161/cc.11.5.19450 · Cited by 98
“The reprogramming of primary (passage 2–4) mouse embryo fibroblasts (MEFs) derived from wild-type embryos (C57BL6 genetic background) was performed as previously described by Marion et al.17 with modifications from a previous protocol by Blelloch et al.136 Briefly, retroviral supernatants were produced in HEK-293T cel…”
BackgroundMethodInfluential
The EMT spectrum and therapeutic opportunities
Voon, D. C., Huang, R. Y., Jackson, R. A., & Thiery, J. P. (2017) · Molecular Oncology · doi:10.1002/1878-0261.12082 · Cited by 99
“A prime example of this would be the role of p53 as a barrier, whereby the loss of its function lowers the threshold for entrance into EMP just as it would enhance the iP efficiency (Ansieau et al., 2008; Austin et al., 2013; Hong et al., 2009; Kawamura et al., 2009; Marion et al., 2009; Mu et al., 2017).”
Background
A TARBP2-Dependent miRNA Expression Profile Underlies Cancer Stem Cell Properties and Provides Candidate Therapeutic Reagents in Ewing Sarcoma
Vito, C. D., Riggi, N., Buros, S. C., Suvà, M.-L., Baumer, K., Provero, P., & Stamenkovic, I. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.04.023 · Cited by 96
“Exactly how CSCs emerge remains unclear but possible mechanisms include transformation of primary stem cells or acquisition of stem cell properties by more differentiated cells as a result of transformation-associated genetic reprogramming (Liu et al., 2009; Marión et al., 2009).”
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Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy
Song, B., Yang, P., & Zhang, S. (2024) · 癌症：英文版 · doi:10.1002/cac2.12520 · Cited by 103
Effective generation of iPS cells from CD34+ cord blood cells by inhibition of p53
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Efficient Generation of Integration-Free iPS Cells from Human Adult Peripheral Blood Using BCL-XL Together with Yamanaka Factors
Su, R. J., Baylink, D. J., Neises, A., Kiroyan, J. B., Meng, X., Payne, K. J., Tschudy-Seney, B., Duan, Y., Appleby, N. C., Kearns‐Jonker, M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064496 · Cited by 100
“[49] Thus, we avoided the use of TP53 shRNA in this study.”
Method
Disruption of Trp53 in Livers of Mice Induces Formation of Carcinomas With Bilineal Differentiation
Katz, S., Lechel, A., Obenauf, A. C., Begus‐Nahrmann, Y., Kraus, J. M., Hoffmann, E. M., Duda, J., Eshraghi, P., Hartmann, D., Liss, B., et al. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.02.009 · Cited by 96
The SIN3A/HDAC Corepressor Complex Functionally Cooperates with NANOG to Promote Pluripotency
Saunders, A., Huang, X., Fidalgo, M., Reimer, M. H., Faiola, F., Ding, J., Sánchez-Priego, C., Guallar, D., Sáenz, C., Li, D., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.01.055 · Cited by 92
“, 2012), and Trp53bp1 (Marión et al., 2009) (Figure 4A, red text) and also identified several downregulated genes known to act as barriers during the reprogramming process (Qin et al.”
NF-κB activation impairs somatic cell reprogramming in ageing
Soria‐Valles, C., Osorio, F. G., Gutiérrez‐Fernández, A., Angeles, A. D. L., Bueno, C., Menéndez, P. R., Martín-Subero, J. I., Daley, G. Q., Freije, J. M. P., & López-Otı́n, C. (2015) · Nature Cell Biology · doi:10.1038/ncb3207 · Cited by 97
Retracted
Ncoa3 functions as an essential Esrrb coactivator to sustain embryonic stem cell self-renewal and reprogrammingPreprint
Percharde, M., Lavial, F., Ng, J.-H., Kumar, V., Tomaz, R. A., Martin, N., Yeo, J.-C., Gil, J., Prabhakar, S., Ng, H., et al. (2012) · Genes & Development · doi:10.1101/gad.195545.112 · Cited by 97
Energy metabolism plasticity enables stemness programs
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Runx3 Protects Gastric Epithelial Cells Against Epithelial-Mesenchymal Transition-Induced Cellular Plasticity and Tumorigenicity
Voon, D. C., Wang, H., Koo, J. K. W., Nguyen, T. A. P., Hor, Y. T., Chu, Y., Ito, K., Fukamachi, H., Chan, S. L., Thiery, J. P., et al. (2012) · Stem Cells · doi:10.1002/stem.1183 · Cited by 93
LIF-Dependent Signaling: New Pieces in the Lego
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The Senescence–Stemness Alliance – A Cancer-Hijacked Regeneration Principle
Milanovic, M., Yu, Y., & Schmitt, C. A. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.09.001 · Cited by 92
The p53 tumor suppressor protein regulates hematopoietic stem cell fate
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“As p53-null HSCs are more proliferative and less quiescent than normal HSCs (Liu et al., 2009), it is possible that mechanisms exist to detect p53-mutated HSCs and limit their inherent advantage (Green, 2010; Marusyk et al., 2010).”
Background
The role of DNA repair in the pluripotency and differentiation of human stem cells
Rocha, C. R. R., Lerner, L. K., Okamoto, O. K., Marchetto, M. C., & Menck, C. F. M. (2012) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2012.09.001 · Cited by 94
Epigenetic Regulation of Nanog by MiR-302 Cluster-MBD2 Completes Induced Pluripotent Stem Cell Reprogramming
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Transcriptional analysis of pluripotency reveals the Hippo pathway as a barrier to reprogramming
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Naked Mole Rat Cells Have a Stable Epigenome that Resists iPSC Reprogramming
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“Next, we compared the efficiencies of the p53 and Rb pathways in NMR and mouse cells, as these two pathways are known to bemajor barriers to reprogramming inmouse and human (Hong et al., 2009; Kawamura et al., 2009; Li et al., 2009; Marion et al., 2009; Utikal et al., 2009).”
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An Induced Pluripotent Stem Cell Model of Hypoplastic Left Heart Syndrome (HLHS) Reveals Multiple Expression and Functional Differences in HLHS-Derived Cardiac Myocytes
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“…to reprogramming into induced pluripotent stem cells (iPSCs) in response to expression of the four Yamanaka factors (Oct3/4, Sox2, Klf4, and c-Myc) (Banito et al. 2009; Hong et al. 2009; Kawamura et al. 2009; Krizhanovsky and Lowe 2009; Li et al. 2009; Marión et al. 2009; Utikal et al. 2009).”
Background
Defining Human Pluripotency
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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)
ORCID: Strati, Katerina
Li, Han
Murga, Matilde
Blanco, Raquel
Ortega, Sagrario
Serrano, Manuel
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2009-08
Volume: 460
Issue: 7259
Pages: 1149-1153
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature08287
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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A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity

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