The study shows that immortalization of cells removes a key barrier to reprogramming into induced pluripotent stem (iPS) cells. Somatic cells with low endogenous ARF levels or those deficient in the p16INK4a/ARF/p53 pathway reprogram more efficiently into iPS cells. This suggests that the loss of replicative potential, associated with cellular senescence, hinders reprogramming. Acute genetic ablation of p53 in cells that normally fail to reprogram rescues their ability to generate iPS cells. The acquisition of immortality is a crucial and rate-limiting step in reprogramming, as it allows cells to bypass senescence-related barriers. Immortalized cells, such as the melanocyte line Melan A, show significantly higher reprogramming efficiency compared to primary cells. This is further supported by the observation that p53 and INK4a/ARF inactivation enhances reprogramming efficiency. The study also shows that the kinetics of reprogramming are faster in immortal cells, with iPS colonies forming in 3-4 days compared to 8 days in wild-type cells. The results indicate that the inactivation of key pathways controlling replicative potential and senescence substantially enhances the reprogramming potential of somatic cells. The study further demonstrates that p53 deficiency allows cells that otherwise fail to reprogram to form iPS cells. The findings highlight the importance of overcoming cellular senescence to achieve efficient reprogramming into iPS cells. The study also shows that the downregulation of the INK4a/ARF locus correlates with the reprogramming process and that the stable silencing of this locus is a late event requiring additional molecular changes. The results suggest that the inactivation of key pathways controlling replicative potential and senescence is critical for efficient reprogramming into iPS cells. The study also shows that the reprogramming efficiency of human cells can be improved by overcoming replicative senescence, as demonstrated by the higher efficiency of hTERT-immortalized keratinocytes compared to primary cells. The findings underscore the importance of overcoming cellular senescence to achieve efficient reprogramming into iPS cells. The study also highlights the potential of immortalized cells as a source for generating iPS cells with high efficiency. The results suggest that the inactivation of key pathways controlling replicative potential and senescence is critical for efficient reprogramming into iPS cells. The study also shows that the reprogramming efficiency of human cells can be improved by overcoming replicative senescence, as demonstrated by the higher efficiency of hTERT-immortalized keratinocytes compared to primary cells. The findings underscore the importance of overcoming cellular senescence to achieve efficient reprogramming into iPS cells.The study shows that immortalization of cells removes a key barrier to reprogramming into induced pluripotent stem (iPS) cells. Somatic cells with low endogenous ARF levels or those deficient in the p16INK4a/ARF/p53 pathway reprogram more efficiently into iPS cells. This suggests that the loss of replicative potential, associated with cellular senescence, hinders reprogramming. Acute genetic ablation of p53 in cells that normally fail to reprogram rescues their ability to generate iPS cells. The acquisition of immortality is a crucial and rate-limiting step in reprogramming, as it allows cells to bypass senescence-related barriers. Immortalized cells, such as the melanocyte line Melan A, show significantly higher reprogramming efficiency compared to primary cells. This is further supported by the observation that p53 and INK4a/ARF inactivation enhances reprogramming efficiency. The study also shows that the kinetics of reprogramming are faster in immortal cells, with iPS colonies forming in 3-4 days compared to 8 days in wild-type cells. The results indicate that the inactivation of key pathways controlling replicative potential and senescence substantially enhances the reprogramming potential of somatic cells. The study further demonstrates that p53 deficiency allows cells that otherwise fail to reprogram to form iPS cells. The findings highlight the importance of overcoming cellular senescence to achieve efficient reprogramming into iPS cells. The study also shows that the downregulation of the INK4a/ARF locus correlates with the reprogramming process and that the stable silencing of this locus is a late event requiring additional molecular changes. The results suggest that the inactivation of key pathways controlling replicative potential and senescence is critical for efficient reprogramming into iPS cells. The study also shows that the reprogramming efficiency of human cells can be improved by overcoming replicative senescence, as demonstrated by the higher efficiency of hTERT-immortalized keratinocytes compared to primary cells. The findings underscore the importance of overcoming cellular senescence to achieve efficient reprogramming into iPS cells. The study also highlights the potential of immortalized cells as a source for generating iPS cells with high efficiency. The results suggest that the inactivation of key pathways controlling replicative potential and senescence is critical for efficient reprogramming into iPS cells. The study also shows that the reprogramming efficiency of human cells can be improved by overcoming replicative senescence, as demonstrated by the higher efficiency of hTERT-immortalized keratinocytes compared to primary cells. The findings underscore the importance of overcoming cellular senescence to achieve efficient reprogramming into iPS cells.