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

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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 rates1,2, 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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Figure 1: p53 -deficiency allows reprogramming of MEFs with short telomeres.
Figure 2: p53 -deficiency abrogates apoptosis at the onset of iPS cell formation.
Figure 3: DDR activation during reprogramming.
Figure 4: p53 -null iPS cells show chromosomal instability.

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Acknowledgements

We thank R. Serrano for mouse colony management, and M. Cañamero and the Comparative Pathology Unit at the CNIO for teratoma analysis. K.S. is recipient of a contract from the Spanish Association Against Cancer (AECC). Work in the laboratory of M.A.B. is funded by grants from the MICINN (CONSOLIDER), the Regional Government of Madrid, the European Union, the European Research Council (ERC), the AECC, and the Korber European Research Award.

Author Contributions R.M.M. and K.S. performed most of the experimental work. H.L., M.M., R.B. and S.O. made critical experimental contributions. R.M.M., K.S., O.F.-C., M.S. and M.A.B. designed the experimental plan, analysed and interpreted the data. M.A.B. directed the project and wrote the paper.

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Correspondence to Maria A. Blasco.

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Marión, R., Strati, K., Li, H. et al. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460, 1149–1153 (2009) doi:10.1038/nature08287

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