As ‘guardian’ of the genome, p53 is a major cellular stress sensor that is activated in response to DNA damage such as telomere dysfunction and to other adverse stimuli such as ROS, oncogene activation and hypoxia. The cellular consequences of p53 activation include growth arrest and repair or apoptosis and senescence, depending on the degree of activation74. In keeping with this role, germline deletion of p53 in mice with critically short telomeres results in a marked decrease in apoptosis and a significant increase in proliferation across many tissues27. The reversal of cellular attrition in the setting of p53 deficiency correlates with improved functionality in organs such as the testes, intestine and skin and in the haematopoietic system. In the skin of late-generation Terc−/− p53−/− mice, there is improved wound healing, hair growth and skin renewal, to levels comparable to those of wild-type mice, as well as increased epidermal stem-cell numbers and improved mobilization capacity75. Similarly, late-generation Terc−/− p53−/− HSCs show improved repopulation capacity in transplantation studies64. Collectively, these data indicate that the p53-dependent telomere checkpoint operates in diverse stem-cell types.
