Grant: Travel Awards - Institute Community Support

Telomeres, located at the extremities of our genetic material, safeguards the DNA from aberrant genetic insults. During normal organismal aging, telomere shortening in somatic, differentiated cells acts as a molecular clock to limit cell proliferation, thereby preventing tumor formation. To sustain self-renewal ability, telomere length in the highly proliferative stem cells and germ cells are normally maintained by a machinery called telomerase. Defective telomere maintenance resulting from insufficient telomerase activity leads to progressive telomere shortening in the stem cell compartments (eg. bone marrow), resulting in the development of premature aging diseases such as dyskeratosis congenital and aplastic anemia. Patients suffering from premature aging syndromes are characterized by extremely short telomeres, bone marrow failure and predisposition to cancer. It has previously been suggested that this predisposition arises as a result of increased genomic instability due to short telomeres. Using murine embryonic stem cells which normally have very long telomeres, we will induce critical telomere erosion to mimic premature aging. We wish to gain a better understanding on genetic events occurring in the presence of telomere instability. We previously showed that critically short telomeres in murine embryonic stem cells can lead to unstable differentiation, allowing the differentiated cells to revert back to a stemness state with unlimited proliferative capacity and resistance to DNA damage. In the present study, we will uncover cellular and molecular mechanisms underlying the unstable stem cell differentiation phenotypes and resistance to DNA damaging agents. The results will have tremendous impact on diagnosis and treatment of premature aging diseases and cancer prevention in these patients.