A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. The study shows that p53 plays a critical role in preventing the reprogramming of cells with DNA damage, including short telomeres, DNA repair deficiencies, or exogenous 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 findings indicate that during reprogramming, cells increase their intolerance to DNA damage, and p53 is critical in preventing the generation of human and mouse pluripotent cells from suboptimal parental cells. The study demonstrates that p53 limits reprogramming by inducing apoptosis of suboptimal cells at the time of pluripotency induction. This effect is exacerbated in cells with a higher proportion of DNA-damaged cells due to dysfunctional telomeres or exogenous DNA damage. The data indicate that p53 becomes sensitized to DNA damage once cells engage the iPS cell program. Direct evidence of p53 activity was observed during iPS cell formation, with a significant proportion of wild-type cells undergoing apoptosis. This was further increased in G3 Terc-/- cultures, which showed lower iPS cell yields. The study also shows that p53-null genotypes exhibit persistent activation of the DNA damage response (DDR), evidenced by the presence of γH2ax and 53BP1 foci. These foci persisted in iPS cell clones and teratomas derived from them, indicating DDR activation during reprogramming. The activity of p53 restricting reprogramming of suboptimal cells is readily observed in wild-type cells and is further exacerbated in G3 Terc-/- cells, which contain a higher proportion of damaged cells. The study also found that p53-null iPS cells showed increased chromosomal damage, including end-to-end fusions and chromosomal breaks/fragments. These findings suggest that p53-deficiency allows reprogramming of G3 Terc-/- cells independently of telomere length. Furthermore, p53-null iPS cells were able to contribute to mouse chimaerism and teratomas, although some showed higher levels of chromosomal damage and DDR activation. In summary, these data indicate that p53 constitutes a main barrier to reprogramming of wild-type cells, which is exacerbated in cells with pre-existing DNA damage or exogenous DNA damage. Suboptimal cells carrying DNA damage are eliminated by p53-dependent apoptosis and prevented from becoming iPS cells. These results agree with previous findings showing that p53 downregulation improves reprogramming efficiency. A p53-dependent counterselection of DNA-damaged cells during reprogramming is shown by increased Atm phosphorylation and increasedA p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. The study shows that p53 plays a critical role in preventing the reprogramming of cells with DNA damage, including short telomeres, DNA repair deficiencies, or exogenous 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 findings indicate that during reprogramming, cells increase their intolerance to DNA damage, and p53 is critical in preventing the generation of human and mouse pluripotent cells from suboptimal parental cells. The study demonstrates that p53 limits reprogramming by inducing apoptosis of suboptimal cells at the time of pluripotency induction. This effect is exacerbated in cells with a higher proportion of DNA-damaged cells due to dysfunctional telomeres or exogenous DNA damage. The data indicate that p53 becomes sensitized to DNA damage once cells engage the iPS cell program. Direct evidence of p53 activity was observed during iPS cell formation, with a significant proportion of wild-type cells undergoing apoptosis. This was further increased in G3 Terc-/- cultures, which showed lower iPS cell yields. The study also shows that p53-null genotypes exhibit persistent activation of the DNA damage response (DDR), evidenced by the presence of γH2ax and 53BP1 foci. These foci persisted in iPS cell clones and teratomas derived from them, indicating DDR activation during reprogramming. The activity of p53 restricting reprogramming of suboptimal cells is readily observed in wild-type cells and is further exacerbated in G3 Terc-/- cells, which contain a higher proportion of damaged cells. The study also found that p53-null iPS cells showed increased chromosomal damage, including end-to-end fusions and chromosomal breaks/fragments. These findings suggest that p53-deficiency allows reprogramming of G3 Terc-/- cells independently of telomere length. Furthermore, p53-null iPS cells were able to contribute to mouse chimaerism and teratomas, although some showed higher levels of chromosomal damage and DDR activation. In summary, these data indicate that p53 constitutes a main barrier to reprogramming of wild-type cells, which is exacerbated in cells with pre-existing DNA damage or exogenous DNA damage. Suboptimal cells carrying DNA damage are eliminated by p53-dependent apoptosis and prevented from becoming iPS cells. These results agree with previous findings showing that p53 downregulation improves reprogramming efficiency. A p53-dependent counterselection of DNA-damaged cells during reprogramming is shown by increased Atm phosphorylation and increased