p53 deficiency rescues the adverse effects of telomere loss and cooperateswith telomere dysfunction to accelerate carcinogenesis

Maintenance of telomere length and function is critical for the efficient p roliferation of eukaryotic cells. Here, we examine the interactions between telomere dysfunction and p53 in cells and organs of telomerase-deficient m ice. Coincident with severe telomere shortening and associated genomic inst ability, p53 is activated, leading to growth arrest and/or apoptosis. Delet ion of p53 significantly attenuated the adverse cellular and organismal eff ects of telomere dysfunction, but only during the earliest stages of geneti c crisis. Correspondingly, the loss of telomere function and p53 deficiency cooperated to initiate the transformation process. Together, these studies establish a key role for p53 in the cellular response to telomere dysfunct ion in both normal and neoplastic cells, question the significance of crisi s as a tumor suppressor mechanism, and identify a biologically relevant sta ge of advanced crisis, termed genetic catastrophe.