| Summary: | Remarkably, the <i>p53</i> transcription factor, referred to as “the guardian of the genome”, is not essential for mammalian development. Moreover, efforts to identify <i>p53</i>-dependent developmental events have produced contradictory conclusions. Given the importance of pluripotent stem cells as models of mammalian development, and their applications in regenerative medicine and disease, resolving these conflicts is essential. Here we attempt to reconcile disparate data into justifiable conclusions predicated on reports that <i>p53</i>-dependent transcription is first detected in late mouse blastocysts, that <i>p53</i> activity first becomes potentially lethal during gastrulation, and that apoptosis does not depend on <i>p53</i>. Furthermore, <i>p53</i> does not regulate expression of genes required for pluripotency in embryonic stem cells (ESCs); it contributes to ESC genomic stability and differentiation. Depending on conditions, <i>p53</i> accelerates initiation of apoptosis in ESCs in response to DNA damage, but cell cycle arrest as well as the rate and extent of apoptosis in ESCs are <i>p53</i>-independent. In embryonic fibroblasts, <i>p53</i> induces cell cycle arrest to allow repair of DNA damage, and cell senescence to prevent proliferation of cells with extensive damage.
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