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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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p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress
Yang, Z., Brož, D. K., Noderer, W. L., Ferreira, J. P., Overton, K. W., Spencer, S. L., Meyer, T., Tapscott, S. J., Attardi, L. D., & Wang, C. L. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.189 · Cited by 48
Chen, M., Zhang, H., Wu, J., Xu, L., Xu, D., Sun, J., He, Y., Zhou, X., Wang, Z., Wu, L., et al. (2012) · Biomaterials · doi:10.1016/j.biomaterials.2012.04.001 · Cited by 44
Cellular reprogramming: a small molecule perspective
Nie, B., Wang, H., Laurent, T., & Ding, S. (2012) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2012.08.010 · Cited by 45
“Consistently, the reprogramming efficiency decreased dramatically in p53BP1 and ATM (both are DNA repair components) knockout cells [10].”
Kane, N. M., Nowrouzi, A., Mukherjee, S., Blundell, M. P., Greig, J. A., Lee, W. K., Houslay, M. D., Milligan, G., Mountford, J. C., Kalle, C. V., et al. (2010) · Molecular Therapy · doi:10.1038/mt.2010.231 · Cited by 44
Wang, B., Pfeiffer, M. J., Drexler, H. C. A., Fuellen, G., & Boiani, M. (2016) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5b01083 · Cited by 43
Lysine methylation represses p53 activity in teratocarcinoma cancer cells
Zhu, J., Dou, Z., Sammons, M. A., Levine, A. J., & Berger, S. L. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1610387113 · Cited by 44
Roles of vitamins in stem cells
Godoy-Parejo, C., Deng, C., Zhang, Y., Liu, W., & Chen, G. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03352-6 · Cited by 45
“Vitamin C reduces cell senescence during reprogramming by suppressing p53 [155, 156].”
BackgroundStress-mediated p38 activation promotes somatic cell reprogramming
Xu, X., Wang, Q., Long, Y., Zhang, R., Wei, X., Xing, M., Gu, H., & Xie, X. (2012) · Cell Research · doi:10.1038/cr.2012.143 · Cited by 41
Anastasia, L., Pelissero, G., Venerando, B., & Tettamanti, G. (2010) · Cell Death and Differentiation · doi:10.1038/cdd.2010.14 · Cited by 44
Schmidt, C. S., Bultmann, S., Meilinger, D., Zacher, B., Tresch, A., Maier, K. C., Peter, C., Martin, D. E., Leonhardt, H., & Spada, F. (2012) · PLoS ONE · doi:10.1371/journal.pone.0052629 · Cited by 44
“proliferative senescence of differentiated cells [67–71].”
Lee, J., Xia, Y., Son, M., Jin, G., Seol, B., Kim, M., Son, M. J., Do, M., Lee, M., Kim, D., et al. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201206691 · Cited by 42
Teichroeb, J. H., Kim, J., & Betts, D. H. (2016) · RNA Biology · doi:10.1080/15476286.2015.1134413 · Cited by 46
“cell lines with critically short telomeres (albeit resulting in widespread chromosomal aberrations).(68) Hence, TERT upregu-”
BackgroundMicroRNAs in regulation of pluripotency and somatic cell reprogramming
Wang, T., Shi, S.-B., & Sha, H. (2013) · RNA Biology · doi:10.4161/rna.25828 · Cited by 42
Patient-Specific Pluripotent Stem Cells in Neurological Diseases
Durnaoglu, S., Genç, Ş., & Genç, K. (2011) · Stem Cells International · doi:10.4061/2011/212487 · Cited by 44
Fukawatase, Y., Toyoda, M., Okamura, K., Nakamura, K.-I., Nakabayashi, K., Takada, S., Yamazaki‐Inoue, M., Masuda, A., Nasu, M., Hata, K., et al. (2014) · Scientific Reports · doi:10.1038/srep05421 · Cited by 41
Voutila, J., Sætrom, P., Mintz, P. J., Sun, G., Alluin, J. V., Rossi, J. J., Habib, N., & Kasahara, N. (2012) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2012.20 · Cited by 42
Tp53 Suppression Promotes Cardiomyocyte Proliferation during Zebrafish Heart Regeneration
Shoffner, A. R., Cigliola, V., Lee, N., Ou, J., & Poss, K. D. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108089 · Cited by 46
“A direct relationship between Tp53 levels and cellular differentiation was also reported in the context of cellular reprogramming, when Tp53 mutant mouse fibroblasts showed increased capacity to undergo conversion to pluripotent cells (Hong et al., 2009; Kawamura et al., 2009; Li et al., 2009; Marión et al., 2009; Uti…”
Telomeres And Telomerase in Adult Stem Cells and Pluripotent Embryonic Stem Cells
Marión, R. M., & Blasco, M. A. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-7037-4_9 · Cited by 46
Self-citationPhysiological cellular reprogramming and cancer
Abollo‐Jiménez, F., Jiménez, R., & Cobaleda, C. (2010) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2010.02.002 · Cited by 42
“[65] Marion RM, Strati K, Li H, Murga M, Blanco R, Ortega S, et al.”
Leonova, K. I., Shneyder, J., Antoch, M. P., Toshkov, I. A., Novototskaya, L. R., Komarov, P. G., Komarova, E. A., & Gudkov, A. V. (2010) · Cell Cycle · doi:10.4161/cc.9.7.11508 · Cited by 40
Therapeutic targeting of the p53 pathway in cancer stem cells
Prabhu, V. V., Allen, J. E., Hong, B., Zhang, S., Cheng, H., & El‐Deiry, W. S. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2012.726985 · Cited by 40
“Five recent papers suggest that p53 acts as a barrier to successful reprogramming of somatic cells and increased reprogramming frequency has been observed in p53-deficient cells [49-56].”
BackgroundGenomic instability during reprogramming by nuclear transfer is DNA replication dependent
Chia, G., Agudo, J., Treff, N. R., Sauer, M. V., Billing, D. L., Brown, B. D., Baer, R. J., & Egli, D. M. (2017) · Nature Cell Biology · doi:10.1038/ncb3485 · Cited by 40
Advances in Gene Therapy for Fanconi Anemia
Rı́o, P., Navarro, S., & Bueren, J. A. (2018) · Human Gene Therapy · doi:10.1089/hum.2018.124 · Cited by 41
“121 One of the first events that occur during the acquisition of pluripotency is the generation of DNA damage, 122 as shown in various studies that found low reprogramming efficiency of uncorrected FA cells because of the inherent DNA repair defects of these cells.”
Genetic aberrations in iPSCs are introduced by a transient G1/S cell cycle checkpoint deficiency
Araki, R., Hoki, Y., Suga, T., Obara, C., Sunayama, M., Imadome, K., Fujita, M., Kamimura, S., Nakamura, M., Wakayama, S., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13830-x · Cited by 42
Didier, N., Hourdé, C., Amthor, H., Marazzi, G., & Sassoon, D. A. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201101075 · Cited by 43
“…activated p53 lead to early onset aging (Cao et al, 2003; Maier et al, 2004; Tyner et al, 2002; Varela et al, 2005; Vogel et al, 1999). p53 is implicated in stem cell regulation (Cicalese et al, 2009; Hong et al, 2009; Kawamura et al, 2009; Li et al, 2009; Marion et al, 2009; TeKippe et al, 2003).”
Looking to the future following 10 years of induced pluripotent stem cell technologies
Li, M., & Belmonte, J. C. I. (2016) · Nature Protocols · doi:10.1038/nprot.2016.108 · Cited by 44
Wang, Y., Chen, S., Jiang, Q., Deng, J. V., Cheng, F., Lin, Y., Cheng, L., Ye, Y., Chen, X., Yao, Y., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2684-9 · Cited by 39
Induced Pluripotent Stem Cells: Emerging Techniques for Nuclear Reprogramming
Han, J. W., & Yoon, Y. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3814 · Cited by 43
“Inhibition of p53 function and Ink4/Arf promotes the reprogramming of somatic cells to pluripotent cells (56, 68, 87, 105, 182).”
BackgroundGuo, Y., Tang, Y., Lu, G., & Gu, J. (2023) · Nutrients · doi:10.3390/nu15102259 · Cited by 40
Cancer as a reprogramming-like disease: Implications in tumor development and treatment
Castellanos‐Martín, A., Vicente‐Dueñas, C., Campos‐Sánchez, E., Cruz, J. J., García‐Criado, F. J., Cenador, M. B. G., Lazo, P. A., Pérez‐Losada, J., & Sánchez-Garcı́a, I. (2010) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2010.02.001 · Cited by 39
Inhibition of PTEN Tumor Suppressor Promotes the Generation of Induced Pluripotent Stem Cells
Liao, J., Marumoto, T., Yamaguchi, S., Okano, S., Takeda, N., Sakamoto, C., Kawano, H., Nii, T., Miyamoto, S., Nagai, Y., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2013.60 · Cited by 40
Tidball, A. M., Neely, M., Chamberlin, R., Aboud, A. A., Kumar, K. K., Han, B., Bryan, M. R., Aschner, M., Ess, K. C., & Bowman, A. B. (2016) · PLoS ONE · doi:10.1371/journal.pone.0150372 · Cited by 35
Common Telomere Changes during In Vivo Reprogramming and Early Stages of Tumorigenesis
Marión, R. M., López de Silanes, I., Mosteiro, L., Gamache, B., Abad, M., Guerra, C., Megías, D., Serrano, M., & Blasco, M. A. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.01.001 · Cited by 39
“Finally, in vitro reprogramming induces epigenetic changes at the telomeric chromatin, including decreased trimethylation of H3K9 and H4K20, indicative of a more ‘‘open’’ chromatin at telomeres (Marion et al., 2009b).”
InfluentialSelf-citationLncRNAs regulating stemness in aging
Sousa‐Franco, A., Rebelo, K., da Rocha, S. T., & de Jesus, B. B. (2018) · Aging Cell · doi:10.1111/acel.12870 · Cited by 38
Mutant p53 subverts p63 control over KLF4 expression in keratinocytes
Cordani, N., Pozzi, S., Martynova, E., Fanoni, D., Borrelli, S., Alotto, D., Castagnoli, C., Berti, E., Viganò, M., & Mantovani, R. (2010) · Oncogene · doi:10.1038/onc.2010.474 · Cited by 42
“This process is influenced by the p53 status (Hong et al., 2009; Kawamura et al., 2009; Marión et al., 2009; Utikal et al., 2009).”
BackgroundThe emerging functions of the p53-miRNA network in stem cell biology
Lin, C.-P., Choi, Y. J., Hicks, G. G., & He, L. (2012) · Cell Cycle · doi:10.4161/cc.20207 · Cited by 38
“The p53-dependent apoptosis was triggered immediately upon the introduction of the classic reprogramming factors and when pluripotency was established.(43,49) The p53 targets that mediate apoptotic response in the context of tumor suppression are well-characterized.”
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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