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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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NKX2.2 Suppresses Self-Renewal of Glioma-Initiating Cells
Muraguchi, T., Tanaka, S., Yamada, D., Tamase, A., Nakada, M., Nakamura, H., Hoshii, T., Ooshio, T., Tadokoro, Y., Naka, K., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-2304 · Cited by 30
“For example, p53 or p16/p19 deficiency increases both the kinetics of induced pluripotent stem (iPS) cell reprogramming and the number of emerging iPS cell colonies (31-35).”
BackgroundVicente‐Dueñas, C., Hauer, J., Ruiz-Roca, L., Ingenhag, D., Rodríguez-Meira, A., Auer, F., Borkhardt, A., & Sánchez-Garcı́a, I. (2014) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2014.02.001 · Cited by 31
Pfaff, N., Lachmann, N., Kohlscheen, S., Sgodda, M., Araúzo-Bravo, M. J., Greber, B., Kues, W. A., Glage, S., Baum, C., Niemann, H., et al. (2011) · Stem Cells and Development · doi:10.1089/scd.2011.0010 · Cited by 30
“For example, mouse embryonic fibroblasts represent a convenient and frequently used starting source for efficient iPSC generation, whereas reprogramming of adult fibroblasts has proven more cumbersome [44,45].”
Inhibition of histone deacetylases enhances DNA damage repair in SCNT embryos
Bohrer, R. C., Duggavathi, R., & Bordignon, V. (2014) · Cell Cycle · doi:10.4161/cc.29215 · Cited by 31
Lats2 is critical for the pluripotency and proper differentiation of stem cells
Aylon, Y., Sarver, A. L., Tovy, A., Ainbinder, E., & Oren, M. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2013.188 · Cited by 29
A patient-derived olfactory stem cell disease model for ataxia-telangiectasia
Stewart, R., Kozlov, S., Matigian, N., Wali, G., Gatei, M. H., Sutharsan, R., Bellette, B., Kijas, A. W., Cochrane, J., Coulthard, M. G., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt101 · Cited by 29
“The low efficiency in human and mouse may be intrinsic to A-T cells because the DNA damage response pathways are activated to remove cells with chromosomal damage during reprograming (46).”
BackgroundItahana, Y., Zhang, J., Göke, J., Vardy, L. A., Han, R., Iwamoto, K., Cukuroglu, E., Robson, P., Pouladi, M. A., Colman, A., et al. (2016) · Scientific Reports · doi:10.1038/srep28112 · Cited by 30
Gadd45a is a heterochromatin relaxer that enhances iPS cell generation
Chen, K., Long, Q., Wang, T., Zhao, D., Zhou, Y., Qi, J., Wu, Y., Li, S., Chen, C., Zeng, X., et al. (2016) · EMBO Reports · doi:10.15252/embr.201642402 · Cited by 37
“On the other hand, the relationship between Gadd45 proteins and p53 is inconsistent as cells activate Gadd45a through p53 under ionic irradiation [43,48], yet p53 is a potent inhibitor of reprogramming [35 – 37] and all Gadd45 proteins have the same effects on reprogramming (Fig 3A).”
p53 and its mutants on the slippery road from stemness to carcinogenesis
Molchadsky, A., & Rotter, V. (2017) · Carcinogenesis · doi:10.1093/carcin/bgw092 · Cited by 30
“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 (145).”
BackgroundProspects for the involvement of cancer stem cells in the pathogenesis of osteosarcoma
Izadpanah, S., Shabani, P., Aghebati‐Maleki, A., Baghbanzadeh, A., Fotouhi, A., Bisadi, A., Maleki, L. A., & Baradaran, B. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.29344 · Cited by 31
Scaffidi, P., & Misteli, T. (2010) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2010.75.007 · Cited by 33
Reprogramming cell fate to pluripotency: the decision-making signalling pathways
Sanges, D., & Cosma, M. P. (2010) · The International Journal of Developmental Biology · doi:10.1387/ijdb.103190ds · Cited by 29
“Indeed, Marión and colleagues (2009) showed that p53-deficient iPSCs are genomically unstable and are not efficient for the production of mice (Marion et al., 2009).”
BackgroundGenome damage in induced pluripotent stem cells: Assessing the mechanisms and their consequences
Hussein, S. M. I., Elbaz, J., & Nagy, A. (2012) · BioEssays · doi:10.1002/bies.201200114 · Cited by 29
“Knockout or downregulation of ATM decreases reprogramming efficiency [19, 25], and mouse iPSCs generated in the absence of ATM do in fact exhibit chromosomal instability [25].”
Dissecting microRNA-mediated regulation of stemness, reprogramming, and pluripotency
Lee, Y. J., Ramakrishna, S., Chauhan, H., Park, W. S., Hong, S., & Kim, K.-S. (2016) · Cell Regeneration · doi:10.1186/s13619-016-0028-0 · Cited by 28
Sivakumar, S., Qi, S., Cheng, N., Sathe, A. A., Kanchwala, M., Kumar, A., Evers, B. M., Xing, C., & Yu, H. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110395 · Cited by 28
“Finally, TP53 inhibits reprogramming of differentiated cells into iPSCs (Hong et al., 2009; Kawamura et al., 2009; Marion et al., 2009).”
BackgroundGenetic instability of modified stem cells - a first step towards malignant transformation?
Steinemann, D., Göhring, G., & Schlegelberger, B. (2013) · Europe PMC (PubMed Central) · Cited by 29
DNA damage response in proliferating Müller glia in the mammalian retina
Nomura-Komoike, K., Saitoh, F., Komoike, Y., & Fujieda, H. (2016) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.15-18101 · Cited by 25
Karpov, D. S., Sosnovtseva, A. O., Pylina, S. V., Bastrich, A., Petrova, D. A., Kovalev, M. A., Shuvalova, A. I., Константиновна, Е. А., & Mokrysheva, N. G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417320 · Cited by 30
“Approaches with transient p53 inhibition led to the genomic instability of the resulting edited iPSC clones [244].”
BackgroundGatekeeper Between Quiescence and Differentiation
Quadrato, G., & Giovanni, S. D. (2012) · International review of neurobiology · doi:10.1016/b978-0-12-398309-1.00005-6 · Cited by 28
“Importantly, in this context, p53 appears to behave as a gatekeeper between pluripotency and differentiation almost functioning as a “reprogramming barrier” to ensure iPS cells’ genome integrity (Marion et al., 2009).”
BackgroundGao, S., Wang, Z., Di, K., Chang, G., Tao, L., An, L., Wu, F., Xu, J., Liu, Y., Wu, Z., et al. (2013) · Journal of Pineal Research · doi:10.1111/jpi.12047 · Cited by 28
Mitochondrial Dynamics: In Cell Reprogramming as It Is in Cancer
Prieto, J., & Torres, J. (2017) · Stem Cells International · doi:10.1155/2017/8073721 · Cited by 26
Cell cycle dynamics in the reprogramming of cellular identity
Hu, X., Eastman, A. E., & Guo, S. (2019) · FEBS Letters · doi:10.1002/1873-3468.13625 · Cited by 28
Human papillomavirus E7 binds Oct4 and regulates its activity in HPV-associated cervical cancers
Panayiotou, T., Michael, S., Zaravinos, A., Demirag, E., Achilleos, C., & Strati, K. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008468 · Cited by 27
“Our findings are consistent with literature and agree with evidence that while proliferation is a necessary co-factor for reprogramming, no conditions have been demonstrated yet where increased proliferation is sufficient [32] to replace any factor during reprogramming.”
ResultSelf-citationThe role of truncated p53 isoforms in the DNA damage response
Reinhardt, L. S., Groen, K., Newton, C., & Avery‐Kiejda, K. A. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188882 · Cited by 31
PTEN and TRP53 Independently Suppress Nanog Expression in Spermatogonial Stem Cells
Kuijk, E., van Mil, A., Brinkhof, B., Penning, L. C., Colenbrander, B., & Roelen, B. A. J. (2009) · Stem Cells and Development · doi:10.1089/scd.2009.0276 · Cited by 28
Liang, Y., Zhang, H., Feng, Q., Cai, M.-B., Deng, W., Qin, D., Yun, J., Tsao, G. S., Kang, T., Esteban, M. A., et al. (2012) · 癌症：英文版 · doi:10.5732/cjc.012.10065 · Cited by 32
Dai, X., Liu, P., Lau, A. W., Liu, Y., & Inuzuka, H. (2014) · Cancer Medicine · doi:10.1002/cam4.298 · Cited by 29
“In support of this idea, recently it has been shown that inactivation of the p53 tumor suppressor pathway greatly enhanced iPS efficiency [25–29], suggesting that key signaling pathway(s), frequently altered in human cancers, might also be involved in stem cell maintenance [30].”
BackgroundWard, C., Volpe, G., Cauchy, P., Ptasinska, A., Almaghrabi, R. O. M., Blakemore, D., Nafria, M., Kestner, D., Frampton, J., Murphy, G. J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.026 · Cited by 26
“We confirmed that the exogenous pluripotent genes were expressed and that the cells infected with OSKB or Tg reprogrammable MEFs infected with Mybl2-AmCyan had not become senescent or apoptotic, two important barriers for the reprogramming process (Banito and Gil, 2010; Hong et al., 2009; Marión et al., 2009; Utikal e…”
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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