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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p53 restricted the stem cell gene expression program.
“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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Cites
Takahashi, K., & Yamanaka, S. (2006) · Cell · doi:10.1016/j.cell.2006.07.024 · Cited by 26,673 · see citing works
Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors
Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007) · Cell · doi:10.1016/j.cell.2007.11.019 · Cited by 20,221 · see citing works
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
Bakkenist, C. J., & Kastan, M. B. (2003) · Nature · doi:10.1038/nature01368 · Cited by 3,466 · see citing works
Reprogramming of human somatic cells to pluripotency with defined factors
Park, I.-H., Zhao, R., West, J. A., Yabuuchi, A., Huo, H.-G., Ince, T., Lerou, P., Lensch, M., & Daley, G. Q. (2008) · Nature · doi:10.1038/nature06534 · Cited by 3,028 · see citing works
Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts
Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K., Ichisaka, T., Aoi, T., Okita, K., Mochiduki, Y., Takizawa, N., & Yamanaka, S. (2007) · Nature Biotechnology · doi:10.1038/nbt1374 · Cited by 2,781 · see citing works
DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis
Bartkova, J., Hořejší, Z., Koed, K., Krämer, A., Tort, F., Zieger, K., Guldberg, P., Sehested, M., Nesland, J. M., Lukas, C., et al. (2005) · Nature · doi:10.1038/nature03482 · Cited by 2,688 · see citing works
In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state
Wernig, M., Meissner, A., Foreman, R. K., Brambrink, T., Ku, M., Hochedlinger, K., Bernstein, B., & Jaenisch, R. (2007) · Nature · doi:10.1038/nature05944 · Cited by 2,669 · see citing works
Vousden, K. H., & Lane, D. P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2147 · Cited by 2,275 · see citing works
Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA
Blasco, M. A., Lee, H.-W., Hande, M. P., Samper, E., Lansdorp, P. M., DePinho, R. A., & Greider, C. W. (1997) · Cell · doi:10.1016/s0092-8674(01)80006-4 · Cited by 2,108 · see citing works
Self-citationOncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication
Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., Schurra, C., Garre’, M., Giovanni Nuciforo, P., Bensimon, A., et al. (2006) · Nature · doi:10.1038/nature05327 · Cited by 1,821 · see citing works
Cellular senescence in cancer and aging.
Collado, M., Blasco, M. A., & Serrano, M. (2007) · Cell · doi:10.1016/j.cell.2007.07.003 · Cited by 1,708 · see citing works
Self-citationAtm-Deficient Mice: A Paradigm of Ataxia Telangiectasia
Barlow, C., Hirotsune, S., Paylor, R. E., Liyanage, M., Eckhaus, M., Collins, F. S., Shiloh, Y., Crawley, J. N., Ried, T., Tagle, D. A., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)80086-0 · Cited by 1,450 · see citing works
Stem Cells, the Molecular Circuitry of Pluripotency and Nuclear Reprogramming
Jaenisch, R., & Young, R. A. (2008) · Cell · doi:10.1016/j.cell.2008.01.015 · Cited by 1,408 · see citing works
Chin, L., Artandi, S. E., Shen, Q., Tam, A., Lee, S.-L., Gottlieb, G. J., Greider, C. W., & DePinho, R. A. (1999) · Cell · doi:10.1016/s0092-8674(00)80762-x · Cited by 979 · see citing works
Oct4-Induced Pluripotency in Adult Neural Stem Cells
Kim, J. B., Sebastiano, V., Wu, G., Araúzo-Bravo, M. J., Sasse, P., Gentile, L., Ko, K., Ruau, D., Ehrich, M., van den Boom, D., et al. (2009) · Cell · doi:10.1016/j.cell.2009.01.023 · Cited by 931 · see citing works
Hochedlinger, K., Yamada, Y., Beard, C., & Jaenisch, R. (2005) · Cell · doi:10.1016/j.cell.2005.02.018 · Cited by 841 · see citing works
Xu, Y., Ashley, T., Brainerd, E. E., Bronson, R. T., Meyn, M. S., & Baltimore, D. (1996) · Genes & Development · doi:10.1101/gad.10.19.2411 · Cited by 830 · see citing works
Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse
Stadtfeld, M., Maherali, N., Breault, D. T., & Hochedlinger, K. (2008) · Cell stem cell · doi:10.1016/j.stem.2008.02.001 · Cited by 823 · see citing works
Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells
Meissner, A., Wernig, M., & Jaenisch, R. (2007) · Nature Biotechnology · doi:10.1038/nbt1335 · Cited by 760 · see citing works
c-Myc Is Dispensable for Direct Reprogramming of Mouse Fibroblasts
Wernig, M., Meissner, A., Cassady, J. P., & Jaenisch, R. (2008) · Cell stem cell · doi:10.1016/j.stem.2007.12.001 · Cited by 627 · see citing works
Telomeres Acquire Embryonic Stem Cell Characteristics in Induced Pluripotent Stem Cells
Marión, R. M., Strati, K., Li, H., Tejera, Á. M., Schoeftner, S., Ortega, S., Serrano, M., & Blasco, M. A. (2009) · Cell stem cell · doi:10.1016/j.stem.2008.12.010 · Cited by 509 · see citing works
Self-citationTelomeres in the mouse have large inter-chromosomal variations in the number of T 2 AG 3 repeats
Zijlmans, J. M. J. M., Martens, U. M., Poon, S. S. S., Raap, A. K., Tanke, H. J., Ward, R. K., & Lansdorp, P. M. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.14.7423 · Cited by 501 · see citing works
Disease states associated with telomerase deficiency appear earlier in mice with short telomeres
Herrera, E., Samper, E., Martín‐Caballero, J., Flores, J. M., Lee, H., & Blasco, M. A. (1999) · The EMBO Journal · doi:10.1093/emboj/18.11.2950 · Cited by 471 · see citing works
Self-citationTwo Supporting Factors Greatly Improve the Efficiency of Human iPSC Generation
Zhao, Y., Yin, X., Qin, H., Zhu, F., Liu, H., Yang, W., Zhang, Q., Xiang, C., Hou, P., Song, Z., et al. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2008.10.002 · Cited by 468 · see citing works
Self-citationp53 Binding Protein 53BP1 Is Required for DNA Damage Responses and Tumor Suppression in Mice
Ward, I. M., Minn, K. T., van Deursen, J., & Chen, J. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.7.2556-2563.2003 · Cited by 412 · see citing works
Samper, E., Goytisolo, F. A., Slijepčević, P., van Buul, P. P. W., & Blasco, M. A. (2000) · EMBO Reports · doi:10.1093/embo-reports/kvd051 · Cited by 317 · see citing works
Self-citationGeneration of Induced Pluripotent Stem Cells in the Absence of Drug Selection
Blelloch, R. H., Venere, M., Yen, J. S., & Ramalho‐Santos, M. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.08.008 · Cited by 278 · see citing works
ATR signaling can drive cells into senescence in the absence of DNA breaks
Toledo, L. I., Murga, M., Gutierrez-Martinez, P., Soria, R., & Fernandez-Capetillo, O. (2008) · Genes & Development · doi:10.1101/gad.452308 · Cited by 183 · see citing works
Self-citationBalancing Out the Ends during iPSC Nuclear Reprogramming
Davy, P. M. C., & Allsopp, R. (2009) · Cell stem cell · doi:10.1016/j.stem.2009.01.004 · Cited by 6 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Epigenetic memory in induced pluripotent stem cells
Kim, K., Doi, A., Wen, B., Ng, K., Zhao, R. C., Cahan, P., Kim, J., Aryee, M. J., Ji, H., Ehrlich, L. I. R., et al. (2010) · Nature · doi:10.1038/nature09342 · Cited by 2,311 · see citing works
The essence of senescence: Figure 1.
Kuilman, T., Michaloglou, C., Mooi, W. J., & Peeper, D. S. (2010) · Genes & Development · doi:10.1101/gad.1971610 · Cited by 2,038 · see citing works
“…and p53 limit the efficiency of iPS cell formation, it has been suggested that cellular senescence counteracts the induced conversion of primary cells into pluripotent stem cells (Banito et al. 2009; Hong et al. 2009; Kawamura et al. 2009; Li et al. 2009; Marión et al. 2009; Utikal et al. 2009).”
BackgroundMutant p53 in Cancer: New Functions and Therapeutic Opportunities
Muller, P. A. J., & Vousden, K. H. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.01.021 · Cited by 1,545 · see citing works
Unravelling mechanisms of p53-mediated tumour suppression
Bieging-Rolett, K. T., Mello, S. S., & Attardi, L. D. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3711 · Cited by 1,389 · see citing works
Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury
Yang, L., Besschetnova, T. Y., Brooks, C. R., Shah, J. V., & Bonventre, J. V. (2010) · Nature Medicine · doi:10.1038/nm.2144 · Cited by 1,333 · see citing works
Cellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270 · see citing works
“Mouse and human fibroblasts silenced for p21 or p53 generate a greater number of induced pluripotent stem (iPS) cell colonies with an accelerated rate, indicating that reprogramming is more efficient when senescence is ablated (23, 162, 180, 219, 322).”
BackgroundMechanisms of disseminated cancer cell dormancy: an awakening field
Sosa, M. S., Bragado, P., & Aguirre‐Ghiso, J. A. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3793 · Cited by 1,125 · see citing works
Somatic coding mutations in human induced pluripotent stem cells
Gore, A., Li, Z., Fung, H.-L., Young, J. E., Agarwal, S., Antosiewicz-Bourget, J., Canto, I., Giorgetti, A., Israel, M. A., Kiskinis, E., et al. (2011) · Nature · doi:10.1038/nature09805 · Cited by 1,273 · see citing works
Direct cell reprogramming is a stochastic process amenable to acceleration
Hanna, J. H., Saha, K., Pando, B., van Zon, J. S., Lengner, C. J., Creyghton, M. P., van Oudenaarden, A., & Jaenisch, R. (2009) · Nature · doi:10.1038/nature08592 · Cited by 1,006 · see citing works
Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells
Loewer, S., Cabili, M. N., Guttman, M., Loh, Y., Thomas, K., Park, I. H., Garber, M. G., Curran, M. S., Önder, T. T., Agarwal, S., et al. (2010) · Nature Genetics · doi:10.1038/ng.710 · Cited by 971 · see citing works
Vitamin C enhances the generation of mouse and human induced pluripotent stem cells.
Esteban, M., Wang, T., Qin, B.-M., Yang, J.-Y., Qin, D.-J., Cai, J.-L., Li, W., Weng, Z., Chen, J.-K., Ni, S., et al. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2009.12.001 · Cited by 989 · see citing works
“While our work was in progress, six independent laboratories identified cell senescence as a roadblock for reprogramming (Hong et al., 2009; Kawamura et al., 2009; Li et al., 2009; Marión et al., 2009; Utikal et al., 2009; Zhao et al., 2008), creating significant interest in finding compounds that alleviate cell senes…”
ResultCopy number variation and selection during reprogramming to pluripotency
Hussein, S. M. I., Batada, N., Vuoristo, S., Ching, R., Autio, R., Närvä, E., Ng, S., Sourour, M., Hämäläinen, R., Olsson, C., et al. (2011) · Nature · doi:10.1038/nature09871 · Cited by 992 · see citing works
Soufi, A., Donahue, G., & Zaret, K. S. (2012) · Cell · doi:10.1016/j.cell.2012.09.045 · Cited by 887 · see citing works
Rivlin, N., Brosh, R., Oren, M., & Rotter, V. (2011) · Genes & Cancer · doi:10.1177/1947601911408889 · Cited by 1,033 · see citing works
The tumorigenicity of human embryonic and induced pluripotent stem cells
Ben-David, U., & Benvenisty, N. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3034 · Cited by 889 · see citing works
A decade of transcription factor-mediated reprogramming to pluripotency
Takahashi, K., & Yamanaka, S. (2016) · Nature reviews. Molecular cell biology · doi:10.1038/nrm.2016.8 · Cited by 815 · see citing works
Cellular senescence and its effector programs
Salama, R., Sadaie, M., Hoare, M., & Narita, M. (2014) · Genes & Development · doi:10.1101/gad.235184.113 · Cited by 855 · see citing works
“Collectively, they suggest that senescence can be a barrier to the reprogramming to generate iPS cells from fibroblasts (Banito et al. 2009; Hong et al. 2009; Kawamura et al. 2009; Li et al. 2009; Marión et al. 2009; Utikal et al. 2009).”
BackgroundInduced pluripotency: history, mechanisms, and applications.Preprint
Stadtfeld, M., & Hochedlinger, K. (2010) · Genes & Development · doi:10.1101/gad.1963910 · Cited by 851 · see citing works
“In addition to its role in conferring immortality on fibroblasts, p53 loss may also contribute to increased reprogramming by inhibiting DNA damage-induced apoptosis (Marion et al. 2009a).”
BackgroundNuclear reprogramming to a pluripotent state by three approaches
Yamanaka, S., & Blau, H. (2010) · Nature · doi:10.1038/nature09229 · Cited by 799 · see citing works
The dynamic nature of senescence in cancer
Lee, S., & Schmitt, C. A. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0249-2 · Cited by 588 · see citing works
Tissue damage and senescence provide critical signals for cellular reprogramming in vivo
Mosteiro, L., Pantoja, C., Alcazar, N., Marión, R. M., Chondronasiou, D., Rovira, M., Fernandez-Marcos, P. J., Muñoz-Martin, M., Blanco-Aparicio, C., Pastor, J., et al. (2016) · Science · doi:10.1126/science.aaf4445 · Cited by 589 · see citing works
“It is well established that Ink4a/Arf, DNA damage, and short telomeres are intrinsic barriers for in vitro reprogramming and, accordingly, in vitro reprogramming efficiency decreases in aged cells (7, 8, 36).”
BackgroundSelf-citationRejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state
Lapasset, L., Milhavet, O., Prieur, A., Besnard, E., Babled, A., Aït-Hamou, N., Leschik, J., Pellestor, F., Ramirez, J.-M., De Vos, J., et al. (2011) · Genes & Development · doi:10.1101/gad.173922.111 · Cited by 570 · see citing works
“It has been reported by several groups that cellular senescence is a barrier to reprogramming due to upregulation of p53, p16, and p21, which are also induced by some of the iPSC reprogramming factors (Banito et al. 2009; Kawamura et al. 2009; Li et al. 2009; Marion et al. 2009a; Utikal et al. 2009).”
BackgroundEpithelial cell polarity, stem cells and cancer
Martín‐Belmonte, F., & Pérez‐Moreno, M. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3169 · Cited by 553 · see citing works
Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins
Martínez, P., & Blasco, M. A. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3025 · Cited by 530 · see citing works
Self-citationCancer stem cells in the development of liver cancer
Yamashita, T., & Wang, X. W. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66024 · Cited by 526 · see citing works
Sox2 expression in breast tumours and activation in breast cancer stem cells
Leis, O., Eguiara, A., López‐Arribillaga, E., Alberdi, M. J., Hernández-García, S., Elorriaga, K., Pandiella, A., Rezola, R., & Martín, Á. G. (2011) · Oncogene · doi:10.1038/onc.2011.338 · Cited by 518 · see citing works
“Recently, the process of reprogramming and tumourigenesis (Kawamura et al., 2009; Li et al., 2009; Marion et al., 2009; Utikal et al., 2009) have been linked as the p53 tumour suppressor, one of the main regulators of oncogenic transformation, controls the induction of pluripotency.”
BackgroundHuman pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations
Merkle, F. T., Ghosh, S., Kamitaki, N., Mitchell, J., Avior, Y., Mello, C., Kashin, S., Mekhoubad, S., Ilic, D., Charlton, M., et al. (2017) · Nature · doi:10.1038/nature22312 · Cited by 506 · see citing works
CHK2 kinase in the DNA damage response and beyond
Zannini, L., Delia, D., & Buscemi, G. (2014) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mju045 · Cited by 455 · see citing works
“It is known that mutations in DDR proteins lower the possibility of success in the stabilization of induced pluripotent stem (iPS) cells, and also that p53 is transiently inactivated during the process of iPS cell generation (Hong et al., 2009; Marion et al., 2009).”
BackgroundExamination of the expanding pathways for the regulation of p21 expression and activity
Jung, Y.-S., Qian, Y., & Chen, X. (2010) · Cellular Signalling · doi:10.1016/j.cellsig.2010.01.013 · Cited by 418 · see citing works
Primordial Germ Cells in MicePreprint
Saitou, M., & Yamaji, M. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008375 · Cited by 418 · see citing works
“Notably, the formation of pluripotent stem cells from spermatogonial stem cells and the induction of pluripotency from somatic cells by defined factors are also enhanced by the lack of p53 function (Kanatsu-Shinohara et al. 2004; Hong et al. 2009; Kawamura et al. 2009; Li et al. 2009; Marion et al. 2009; Utikal et al.…”
BackgroundPromotion of direct reprogramming by transformation-deficient Myc
Nakagawa, M., Takizawa, N., Narita, M., Ichisaka, T., & Yamanaka, S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1009374107 · Cited by 403 · see citing works
Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State
Garcı́a-Cao, I., Song, M. S., Hobbs, R. M., Laurent, G., Giorgi, C., de Boer, V. C. J., Anastasiou, D., Ito, K., Sasaki, A. T., Rameh, L. E., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.030 · Cited by 403 · see citing works
Zou, M., Toivanen, R., Mitrofanova, A., Floc’h, N., Hayati, S., Sun, Y., Magnen, C. L., Chester, D., Mostaghel, E. A., Califano, A., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-1174 · Cited by 380 · see citing works
“In contrast, a general role for the p53 pathway in regulating cellular reprogramming has been previously suggested by studies showing that inhibition of p53 pathway activity results in increased efficiency in the formation of induced pluripotent stem cells (43-47).”
BackgroundmiR-34 miRNAs provide a barrier for somatic cell reprogramming
Choi, Y. J., Lin, C., Ho, J. J., He, X., Okada, N., Bu, P., Zhong, Y., Kim, S. Y., Bennett, M. J., Chen, C., et al. (2011) · Nature Cell Biology · doi:10.1038/ncb2366 · Cited by 381 · see citing works
“…, mir-34 miRNAs and p21 are the major downstream targets that cooperatively repress iPSC generation. p53 effects on reprogramming reflect changes in cell proliferation, immortalization, apoptosis, and DNA damage response 4, 5, 12 . p21, a key downstream target of p53, represses cell proliferation.”
Panich, U., Sittithumcharee, G., Rathviboon, N., & Jirawatnotai, S. (2016) · Stem Cells International · doi:10.1155/2016/7370642 · Cited by 374 · see citing works
“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].”
Genetic and Epigenetic Variations in iPSCs: Potential Causes and Implications for Application
Liang, G., & Zhang, Y. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.07.001 · Cited by 368 · see citing works
Induced Pluripotent Stem Cells and Their Use in Human Models of Disease and Development
Karagiannis, P., Takahashi, K., Saito, M. K., Yoshida, Y., Okita, K., Watanabe, A., Inoue, H., Yamashita, J. K., Todani, M., Nakagawa, M., et al. (2018) · Physiological Reviews · doi:10.1152/physrev.00039.2017 · Cited by 367 · see citing works
NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes
Sosa, M. S., Parikh, F., Gaspar‐Maia, A., Estrada, Y. D., Bosch, A., Bragado, P., Ekpin, E., George, A. D., Zheng, Y., Lam, H., et al. (2015) · Nature Communications · doi:10.1038/ncomms7170 · Cited by 357 · see citing works
The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein
Feng, Z., & Levine, A. J. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.03.004 · Cited by 359 · see citing works
Ruiz, S., Panopoulos, A. D., Herrerias, A., Bissig, K., Lutz, M. K., Berggren, W. T., Verma, I. M., & Belmonte, J. C. I. (2010) · Current Biology · doi:10.1016/j.cub.2010.11.049 · Cited by 317 · see citing works
Role of Sirtuin1-p53 regulatory axis in aging, cancer and cellular reprogramming
Ong, A. L. C., & Ramasamy, T. S. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.02.004 · Cited by 301 · see citing works
Cellular senescence in development, regeneration and disease
Rhinn, M., Ritschka, B., & Keyes, W. M. (2019) · Development · doi:10.1242/dev.151837 · Cited by 296 · see citing works
“…genes p53, p16INK4A, p19ARF or p21 significantly increases the efficiency of reprogramming, demonstrating that cell-intrinsic senescence is a barrier to 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).”
BackgroundProgress in understanding reprogramming to the induced pluripotent state
Plath, K., & Lowry, W. E. (2011) · Nature Reviews Genetics · doi:10.1038/nrg2955 · Cited by 285 · see citing works
Redox homeostasis: the linchpin in stem cell self-renewal and differentiation
Wang, K., Zhang, T., Dong, Q. G., Nice, E. C., Huang, C., & Wei, Y. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.50 · Cited by 291 · see citing works
Riggi, N., Suvà, M.-L., Vito, C. D., Provero, P., Stehle, J., Baumer, K., Cironi, L., Janiszewska, M., Petricevic, T., Suvà, D., et al. (2010) · Genes & Development · doi:10.1101/gad.1899710 · Cited by 279 · see citing works
“In addition, recent observations suggest that two major tumor suppressor genes, INK4A and TP53, impair efficient iPS generation (Banito et al. 2009; Kawamura et al. 2009; Marion et al. 2009), consistent with the existence of a relationship between genetic reprogramming and transformation.”
BackgroundThe promises and perils of p53
Krizhanovsky, V., & Lowe, S. W. (2009) · Nature · doi:10.1038/4601085a · Cited by 274 · see citing works
Li, M., He, Y., Dubois, W., Wu, X., Shi, J., & Huang, J. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.01.020 · Cited by 264 · see citing works
“p53 in Reprogramming p53-mediated DNA damage response is one of the major barriers for reprogramming (Kawamura et al., 2009; Marión et al., 2009).”
InfluentialInduced Pluripotent Stem Cells 10 Years Later
Yoshida, Y., & Yamanaka, S. (2017) · Circulation Research · doi:10.1161/circresaha.117.311080 · Cited by 266 · see citing works
Ohnuki, M., Tanabe, K., Sutou, K., Teramoto, I., Sawamura, Y., Narita, M., Nakamura, M., Tokunaga, Y., Nakamura, M., Watanabe, A., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1413299111 · Cited by 256 · see citing works
Induced pluripotent stem cells: opportunities and challenges
Okita, K., & Yamanaka, S. (2011) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2011.0016 · Cited by 259 · see citing works
SIRT1 contributes to telomere maintenance and augments global homologous recombination
Palacios, J., Herranz, D., Bonis, M. L. D., Velasco, S., Serrano, M., & Blasco, M. A. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.201005160 · Cited by 254 · see citing works
“To rule out this apparent lack of SIRT1 binding to telomeric repeats as the result of a transient association, we set to perform SIRT1 ChIP analysis in cells with very long telomeres such as those of pluripotent stem cells (Flores et al., 2008; Marion et al., 2009b).”
Self-citationDirect lineage conversions: unnatural but useful?
Vierbuchen, T., & Wernig, M. (2011) · Nature Biotechnology · doi:10.1038/nbt.1946 · Cited by 259 · see citing works
p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer
Tschaharganeh, D. F., Xue, W., Calvisi, D. F., Evert, M., Michurina, T. V., Dow, L. E., Banito, A., Katz, S. F., Kastenhuber, E. R., Weissmueller, S., et al. (2014) · Cell · doi:10.1016/j.cell.2014.05.051 · Cited by 227 · see citing works
p53 Regulates Cell Cycle and MicroRNAs to Promote Differentiation of Human Embryonic Stem Cells
Jain, A. K., Allton, K. L., Iacovino, M., Mahen, E. M., Milczarek, R. J., Zwaka, T. P., Kyba, M., & Barton, M. C. (2012) · PLoS Biology · doi:10.1371/journal.pbio.1001268 · Cited by 226 · see citing works
Deconstructing networks of p53-mediated tumor suppression in vivo
Kaiser, A. M., & Attardi, L. D. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.171 · Cited by 227 · see citing works
Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells
Liu, C., Yin, Q., Zhou, H., Wu, Y., Pu, J., Li, X., Liu, W., Huang, X. Y., Jiang, T., Wu, M., et al. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.935 · Cited by 222 · see citing works
Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective
Liang, G., & Zhang, Y. (2012) · Cell Research · doi:10.1038/cr.2012.175 · Cited by 223 · see citing works
DNA methylation and cellular reprogramming
Carvalho, D. D. D., You, J. S., & Jones, P. A. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.08.003 · Cited by 219 · see citing works
“More recently, it has been shown that cell cycle control checkpoints, mediated by the INK4aARF locus and p53, limit reprogramming, and disruption of these pathways enhances iPSC generation [13,14,15,16,17].”
BackgroundCellular Differences in Protein Synthesis Regulate Tissue Homeostasis
Buszczak, M., Signer, R. A. J., & Morrison, S. J. (2014) · Cell · doi:10.1016/j.cell.2014.09.016 · Cited by 215 · see citing works
Pluripotent Stem Cells: Current Understanding and Future Directions
Romito, A., & Cobellis, G. (2015) · Stem Cells International · doi:10.1155/2016/9451492 · Cited by 224 · see citing works
“Several groups also observed that expression of reprogramming factors activates the DNA damage response (DDR) pathway [128–130].”
Lack of p21 expression links cell cycle control and appendage regeneration in mice
Bedelbaeva, K., Snyder, A., Gourevitch, D., Clark, L., Zhang, X.-M., Leferovich, J., Cheverud, J. M., Lieberman, P., & Heber-Katz, E. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1000830107 · Cited by 207 · see citing works
“DNA damage can be tolerated during cellular reprogramming, apoptosis can ensue if the levels are too high (48).”
BackgroundDynamic single-cell imaging of direct reprogramming reveals an early specifying event
Smith, Z. D., Nachman, I., Regev, A., & Meissner, A. (2010) · Nature Biotechnology · doi:10.1038/nbt.1632 · Cited by 205 · see citing works
Omole, A. E., & Fakoya, A. O. J. (2018) · PeerJ · doi:10.7717/peerj.4370 · Cited by 207 · see citing works
“As was mentioned in reprogramming factors–cell cycle regulating genes, p53 tumor suppressor proteins have inhibitory effects on iPSC generation by promoting senescence, apoptosis and cell cycle inhibition (Kawamura et al., 2009; Marion et al., 2009; Utikal et al., 2009b; Hong et al., 2009; Banito et al., 2009).”
BackgroundMarqués‐Torrejón, M. Á., Porlan, E., Banito, A., Gómez-Ibarlucea, E., Lopez-Contreras, A. J., Fernández-Capetillo, Ó., Vidal, A., Gil, J., Torres, J., & Fariñas, I. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.12.001 · Cited by 199 · see citing works
“Moreover, overexpression of reprogramming factors results in increased proportions of cells displaying senescent features (Banito et al., 2009; Hong et al., 2009; Kawamura et al., 2009; Marión et al., 2009; Li et al., 2009; Banito and Gil, 2010).”
InfluentialTargeting FAK in human cancer: from finding to first clinical trials
Golubovskaya, V. (2014) · Frontiers in bioscience · doi:10.2741/4236 · Cited by 197 · see citing works
Ji, J., Ng, S. H. S., Sharma, V., Neculai, D., Hussein, S. M. I., Sam, M., Trinh, Q. M., Church, G. M., McPherson, J. D., Nagy, A., et al. (2011) · Stem Cells · doi:10.1002/stem.1011 · Cited by 191 · see citing works
Telomeres in cancer and ageing
Donate, L. E., & Blasco, M. A. (2010) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2010.0291 · Cited by 189 · see citing works
Self-citationReprogramming to pluripotency: stepwise resetting of the epigenetic landscape
Papp, B., & Plath, K. (2011) · Cell Research · doi:10.1038/cr.2011.28 · Cited by 187 · see citing works
Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics
Bogliolo, M., & Surrallés, J. (2015) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2015.07.002 · Cited by 184 · see citing works
Mosteiro, L., Pantoja, C., de Martino, A., & Serrano, M. (2018) · Aging Cell · doi:10.1111/acel.12711 · Cited by 182 · see citing works
“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-citationCai, J.-L., Li, W., Su, H.-X., Qin, D.-J., Yang, J.-Y., Zhu, F., Xu, J.-Y., He, W., Guo, X., Labuda, K., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.086389 · Cited by 184 · see citing works
Zunder, 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 177 · see citing works
“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 179 · see citing works
Mallanna, S. K., & Rizzino, A. (2010) · Developmental Biology · doi:10.1016/j.ydbio.2010.05.014 · Cited by 180 · see citing works
“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 180 · see citing works
“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 180 · see citing works
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 177 · see citing works
“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 · see citing works
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 173 · see citing works
“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 175 · see citing works
“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 · see citing works
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 166 · see citing works
“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
Zhao, Z., Zuber, J. A., Díaz-Flores, E., Lintault, L., Kogan, S. C., Shannon, K., & Lowe, S. W. (2010) · Genes & Development · doi:10.1101/gad.1940710 · Cited by 167 · see citing works
“…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 164 · see citing works
“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 · see citing works
Role of shelterin in cancer and aging
Martínez, P., & Blasco, M. A. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00596.x · Cited by 162 · see citing works
“pigmentation and female obesity Martinez et al., (2010) Role of shelterin in cancer and aging, P.”
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 · see citing works
“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 161 · see citing works
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 159 · see citing works
Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures
Mizuno, H., Spike, B. T., Wahl, G. M., & Levine, A. J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1017001108 · Cited by 159 · see citing works
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 158 · see citing works
Mehta, S. V., Huillard, E., Kesari, S., Maire, C. L., Golebiowski, D., Harrington, E. P., Alberta, J. A., Kane, M., Theisen, M., Ligon, K. L., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.01.035 · Cited by 158 · see citing works
“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 154 · see citing works
Ubiquitin‐specific proteases 7 and 11 modulate Polycomb regulation of the INK4a tumour suppressor
Maertens, G. N., Messaoudi, S. E., Elderkin, S., Hiom, K. J., & Peters, G. G. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.129 · Cited by 155 · see citing works
“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 156 · see citing works
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 156 · see citing works
“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
Warren, L., Ni, Y., Wang, J., & Guo, X. (2012) · Scientific Reports · doi:10.1038/srep00657 · Cited by 154 · see citing works
Sarig, R., Rivlin, N., Brosh, R., Bornstein, C., Kamer, I., Ezra, O., Molchadsky, A., Goldfinger, N., Brenner, O. J., & Rotter, V. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20100797 · Cited by 155 · see citing works
“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).”
BackgroundResultInfluentialZhao, W., Li, Q., Ayers, S. D., Gu, Y., Shi, Z. Q., Zhu, Q., Chen, Y., Wang, H. Y., & Wang, R. (2013) · Cell · doi:10.1016/j.cell.2013.02.006 · Cited by 148 · see citing works
“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 152 · see citing works
Self-citation
- 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
- Health Sciences › Medicine › Physiology › 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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