Senior Scholar Award in Aging
Ronald A. DePinho, M.D.
Dana Farber Cancer Institute

The Genetic Role of Telomere Dynamics and DNA Damage Response in Stem Cell Depletion, Organ Homeostasis and Aging

Telomeres are specialized capping structures on chromosomes that play important roles in aging, cancer and genome stability. Normal cells do not possess the specialized enzyme telomerase that functions to synthesize and maintain telomere length with each cell division. Thus, cell division is associated with progressive telomere shortening and activation of growth arrest mechanisms, a cellular response that limits the replicative potential of normal cells and the potential for cancer growth. Mutations in the p53 tumor suppressor gene allows cells to bypass this growth arrest phase, resulting in continued telomere erosion and ultimately loss of capping function, chromosomal instability and massive cell death. This period of instability and death, termed crisis, serves to generate the large number of changes needed for malignant transformation. Eventually, telomerase activation stabilizes cells with the appropriate constellation of pro-cancer changes, endowing cells with indefinitely growth potential. As mice cells have dramatically longer telomeres than those of humans, mouse cells do not experience crisis when they become cancerous. We have recently generated a mutant mouse that is deficient for telomerase activity. When these mice are bred for successive generations to shorten ("humanize") their telomeres and in conjunction with other mutations, these mice develop epithelial cancer whose genetic makeup is very similar to those seen in human epithelial cancers.

The importance of p53 in modulating the ‘short’ telomere response prompted us to explore the biological impact of other components in the p53 pathway, including ATM. In humans, loss of ATM function is associated with the disease, Ataxia-telangiectasia (A-T), an autosomal recessive disease characterized by genomic instability, hypersensitivity to ionizing radiation, progressive neuronal degeneration, accelerated aging, and high incidence of cancers. The pleiotropic nature of A-T reflects loss of Ataxia-Telangiectasia Mutated (ATM) function, a kinase known to play pivotal roles in diverse processes including telomere maintenance and DNA damage signaling/repair responses. We recently generated Atm mutant mice with "humanized" telomeres, and showed that these mice more closely resembled humans with A-T: e.g. multi-organ system failure, stem cell depletion, premature aging and death, implicating telomere dynamics in the pathogenesis of AT. We now wish to extend these findings by trying to understand the role of the crucial ATM target, p53, in mediating these phenotypes seen in Atm mutant mice with "humanized" telomeres. We will generate and analyze cohorts of triple compound mutant (telomerase, Atm and p53) mice with varying telomere length and function. In addition, we will reconstitute telomerase activity in various organs of these mice to determine the impact telomerase and telomere maintenance play in aging and tumorigenesis. In addition, these unique mutant mice represent an excellent model of global stem cell depletion and also sustain classical progressive Parkinson’s disease (a common and progressive neurodegenerative condition in A-T patients). Thus, this model system will also be used as a platform to assess the therapeutic impact of stem cell reconstitution. These studies will facilitate a better fundamental understanding of the role ATM, p53 and telomerase play in aging and cancer and the utility of stem cell therapy in progressive degenerative conditions.

Contact Dr. DePinho.