Short telomeres: Consequences and mechanisms

The ends of linear chromosomes, telomeres, stand at the molecular crossroads of cellular ageing and immortality. With each cellular division, the telomere shortens, thereby measuring the replicative history of the cell. Eventually, telomere erosion elicits a DNA damage response, halting the cell cycle and initiating programs of cellular senescence or apoptosis. Telomere length regulation is therefore a barrier to cellular immortality. Immortal cells, both normal (i.e. germ cells) and most malignant cells maintain telomeres by expression of a specialized reverse transcriptase, telomerase. The highly regulated nature of telomerase expression has led many to propose that inhibition of telomerase would yield great therapeutic potential in the treatment of cancer.; In this dissertation, I have explored the mechanism by which the telomerase enzyme is recruited to its substrate, the telomere, and the consequences of telomerase inhibition during tumorigenesis. Within, I show that a commonly held assumption, that the Ataxia telangiectasia mutated kinase is required for telomerase-mediated telomere addition, is not true. In addition, although replicative senescence was first described in seminal experiments by Hayflick and Morehead some forty years ago, direct experimental evidence that this was a tumor suppressor mechanism was lacking. Using a mouse model of Burkitt's lymphoma, I show that short telomeres provided a 75% tumor free survival compared to 0% tumor free survival in long telomere controls. Mechanistically, short telomeres selected for loss of both apoptotic and senescence pathways in the tumors that did arise in the short telomere animals. Loss of the apoptotic pathway, alone, was not sufficient for tumorigenesis in the presence of short telomeres due to the initiation of a p53-dependent senescence program. In a second tumor model, I provide compelling evidence that short telomeres can delay the onset of chronic myeloid leukemia induced by expression of the Bcr-Abl oncogene in mouse bone marrow cells. These experimental observations, exemplify the clinical potential of telomerase therapy in many different cancers. Thus, due to the multiple tumor suppressor mechanisms that short telomeres initiate, telomerase inhibition in a clinical setting may be beneficial in the treatment of human malignancy.