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

Marión, Rosa M.; Strati, Katerina; Li, Han; Murga, Matilde; Blanco, Raquel; Ortega, Sagrario; Fernández-Capetillo, Óscar; Serrano, Manuel; Blasco, Marı́a A.

doi:10.1038/nature08287

Cited by 938 publications

(912 citation statements)

References 29 publications

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“…Only a few cells can overcome this barrier and become iPSCs. A number of studies demonstrated that when key components (such as p53 and p21) of the DNA damage pathway were deleted, the percentage of iPS cell generation significantly increased (Zhao et al, 2008a;Banito et al, 2009;Hong et al, 2009;Kawamura et al, 2009;Li et al, 2009;Marión et al, 2009;Utikal et al, 2009b). Suppression of the p53 pathway may compromise a cell's genome stability.…”

Section: Overcoming the Dna Damage Responsementioning

confidence: 99%

“…As the DNA damage pathway poses a major barrier towards regaining pluripotency (Zhao et al, 2008b;Banito et al, 2009;Hong et al, 2009;Kawamura et al, 2009;Li et al, 2009;Marión et al, 2009;Utikal et al, 2009b), chemical compounds that alleviate the stress of DNA damage response may help cells to overcome this barrier. To this end, Vitamin C has been shown to significantly increase the formation of both mouse and human iPSC by suppressing p53 induced cell senescence (Esteban et al, 2010).…”

Section: Chemical Compoundsmentioning

confidence: 99%

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Mechanism and methods to induce pluripotency

Wang

2011

Protein Cell

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Pluripotent stem cells are able to self-renew indefinitely and differentiate into all types of cells in the body. They can thus be an inexhaustible source for future cell transplantation therapy to treat degenerative diseases which currently have no cure. However, non-autologous cells will cause immune rejection. Induced pluripotent stem cell (iPSC) technology can convert somatic cells to the pluripotent state, and therefore offers a solution to this problem. Since the first generation of iPSCs, there has been an explosion of relevant research, from which we have learned much about the genetic networks and epigenetic landscape of pluripotency, as well as how to manipulate genes, epigenetics, and microRNAs to obtain iPSCs. In this review, we focus on the mechanism of cellular reprogramming and current methods to induce pluripotency. We also highlight new problems emerging from iPSCs. Better understanding of the fundamental mechanisms underlying pluripotenty and refining the methodology of iPSC generation will have a significant impact on future development of regenerative medicine.

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Section: Overcoming the Dna Damage Responsementioning

confidence: 99%

Section: Chemical Compoundsmentioning

confidence: 99%

Mechanism and methods to induce pluripotency

Wang

2011

Protein Cell

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“…Thus, overexpression of this TF has profound and lasting consequences on the expression of growth-promoting genes. This process is influenced by the p53 status Kawamura et al, 2009;Mario´n et al, 2009;Utikal et al, 2009).…”

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confidence: 99%

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

et al. 2010

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Genetic experiments established that p63 is crucial for the development and maintenance of pluri-stratified epithelia and KLF4 for the barrier function of the skin. KLF4 is one of the factors that reprogram differentiated cells to iPS. We investigated the relationship between p63 and KLF4 using RNA interference, overexpression, chromatin immunoprecipitation and transient transfections with reporter constructs. We find that p63 directly represses KLF4 in normal keratinocytes (KCs) by binding to upstream promoter sites. Unlike p63, KLF4 levels are high in the upper layers of human skin and increase upon differentiation of KCs in vitro. In HaCaT KCs, which harbor two mutant alleles of p53, inactivation of p63 and of mutant p53 leads to KLF4 repression. p63 and p53 mutants are bound to sites in the KLF4 core promoter. Importantly, expression of the H179Y and R282Q p53 mutants in primary KCs is sufficient to activate endogenous KLF4. Finally, immunohistochemical analysis of tissue arrays confirms increased coexpression of KLF4 and mutant p53 in squamous cell carcinomas. Our data indicate that suppression of KLF4 is part of the growth-promoting strategy of p63 in the lower layers of normal epidermis, and that tumor-predisposing p53 mutations hijack p63 to a different location on the promoter, turning it into an activator of this reprogramming factor.

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“…We speculate that p53 or p63 enrichment on myogenin regulatory elements previously observed in non-myogenic cells, such as MEFs, 41 mESC, 42 or primary keratinocytes, 46 may reflect a poised global surveillance system that maintains cell identity and prevents, at least, a myogenic fate transition in response to stress signals. This notion is supported by the observation that elimination of p53 enhances cellular plasticity and efficiency of reprogramming somatic cells to pluripotency 58 and differentiated hepatocytes to malignant cell fates. 59 Intriguingly, under the differentiation condition we observed short-term p53 binding, loss of myogenin repression, and recovery of late-stage differentiation post IR.…”

Section: Discussionmentioning

confidence: 87%

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

et al. 2014

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Acute muscle injury and physiological stress from chronic muscle diseases and aging lead to impairment of skeletal muscle function. This raises the question of whether p53, a cellular stress sensor, regulates muscle tissue repair under stress conditions. By investigating muscle differentiation in the presence of genotoxic stress, we discovered that p53 binds directly to the myogenin promoter and represses transcription of myogenin, a member of the MyoD family of transcription factors that plays a critical role in driving terminal muscle differentiation. This reduction of myogenin protein is observed in G1-arrested cells and leads to decreased expression of late but not early differentiation markers. In response to acute genotoxic stress, p53-mediated repression of myogenin reduces post-mitotic nuclear abnormalities in terminally differentiated cells. This study reveals a mechanistic link previously unknown between p53 and muscle differentiation, and suggests new avenues for managing p53-mediated stress responses in chronic muscle diseases or during muscle aging. Cell Death and Differentiation (2015) 22, 560-573; doi:10.1038/cdd.2014; published online 12 December 2014The tumor suppressor p53 promotes cell cycle arrest or apoptosis in response to diverse stress signals such as DNA damage, thus preventing propagation of genetically compromised cells. [1][2][3] Among the diverse functions attributed to p53, a growing body of evidence supports its role in regulation of differentiation and maintenance of cellular function and integrity. 1,[4][5][6][7] For example, p53 represses Nanog to maintain genetic stability of the stem cell pool by promoting differentiation of mouse embryonic stem cells (mESCs) after DNA damage. 6 Skeletal muscle differentiation, a key step during muscle tissue formation, is orchestrated by the MyoD family of myogenic regulatory factors (MRFs). MyoD determines the myogenic lineage, whereas myogenin, a member of the MRF family, functions downstream of MyoD and plays a critical role in driving terminal differentiation as myogenin-null mice show a lethal deficiency of differentiated skeletal muscle. [8][9][10][11][12][13] The dynamic differentiation program of skeletal muscle is characterized by the orderly expression of genes and structural changes that can be recapitulated in vitro, as myogenic cells undergo cell cycle withdrawal and express early and then late differentiation genes with the formation of mononucleated myocytes to elongated multinucleated myotubes. 8,9,14 Under normal unstressed conditions, p53 has been shown to promote muscle differentiation in vitro. [15][16][17][18][19][20] In contrast, under stress-associated conditions such as inflammation, chronic exposure to double-strand DNA breaks, and aging, enhanced p53 activity has been shown to correlate with skeletal muscle atrophy in vivo. [21][22][23][24][25] In addition, it has been shown that p53 and its downstream effectors are required for an inflammatory cytokine-mediated inhibition of myogenic differentiation in vitro. 22 Int...

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

Cited by 938 publications

References 29 publications

Mechanism and methods to induce pluripotency

Mechanism and methods to induce pluripotency

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

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