title: A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity.
abstract: 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.
authors: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, Madrid E-28029, Spain.
authors: Rosa M
authors: RM
authors: Marión
authors: Katerina
authors: K
authors: Strati
authors: Han
authors: H
authors: Li
authors: Matilde
authors: M
authors: Murga
authors: Raquel
authors: R
authors: Blanco
authors: Sagrario
authors: S
authors: Ortega
authors: Oscar
authors: O
authors: Fernandez-Capetillo
authors: Manuel
authors: M
authors: Serrano
authors: Maria A
authors: MA
authors: Blasco
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000502:physiology*; D002869:Chromosome Aberrations; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D042822:Genomic Instability / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53