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

By R. M. Marión, K. Strati, Han Li, M. Murga, R. Blanco, Sagrario Ortega, O. Fernández-Capetillo, Manuel Serrano, M. Blasco. Nature, 2009

1,065 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/1f0bd26505c910e5162e3204d11b785dedbd0402

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Citations in the corpus

Cellular senescence and its effector programs (2014, background): “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).”
Senescence impairs successful reprogramming to pluripotent stem cells. (2009, background): “…time that the work present here was published, several groups showed that knocking down p53 or its transcriptional target CDKN1a in human or mouse cells can significantly increase the efficiency of reprogramming (Hong et al., 2009; Kawamura et al., 2009; Marion et al., 2009a; Utikal et al., 2009).”
Induced pluripotency: history, mechanisms, and applications. (2010, background): “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).”
Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. (2010, result): “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 a”
Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “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).”
The essence of senescence. (2010, background): “…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).”