Grant: Operating Grant

Cells have evolved a complex system to maintain the integrity of chromosome ends or telomeres. In humans, telomeres contain thousands of repeats of a simple 6-base pair sequence. In many cell types, the enzyme telomerase adds new telomere repeats during the process of genome duplication, and this maintenance allows the telomere to maintain a protective cap through many cell divisions. In cancer, although telomerase is often activated and telomeres are functional enough to permit cell division, the average telomere length is usually short. We recently made an unexpected discovery that short telomeres prevented the ability of cell precursors called stem cells to give rise to and maintain the stable, specialized cell types that make up our various tissues. Cancer cells, like stem cells, can also be prodded to differentiate into other cell types. In fact, agents that promote differentiation are employed in the treatment of several types of cancer. One current clinical problem is that cancer cells can develop resistance to these differentiation-inducing treatments. The recent finding that elongation of chromosome ends improves the response of cancers to differentiation supports the idea that telomere integrity is intricately linked to stable cell function. The mechanism(s) by which this happens are, as yet, largely unknown. Our goal is to understand the precise means by which telomere integrity influences the ability of stem cells and cancer cells to maintain stable cell function. At the conclusion of these studies, we hope to understand and to experimentally influence how telomere integrity influences cancer cells and stem cells to adopt and maintain a non-cancerous cell fate.