MERIT Award Recipient: Ronald A. DePinho, M.D.
Telomerase in Development, Senescence and Neoplasia
Advancing age is the most important risk factor for the development of human cancers, particularly epithelial cancers. The genomic profiles of epithelial cancers are characterized by many chromosomal structural alterations such as amplifications, deletions and translocations, all of which interfere with the normal regulation of cell behavior. Telomeres, which serve as caps at the ends of all cells' chromosomes, play a critical role in shaping cancer genomes. During normal aging and the early phases of cancers, telomeres are gradually eroded due to insufficient levels of a telomere-synthesizing enzyme, telomerase; this telomere shortening results in chromosomal end fusions and cycles of chromosomal breakage during cell division. As a cellular "quality control" mechanism, the breakage of DNA normally results in activation of the p53 tumor suppressor protein, eliciting cellular checkpoint responses including cell cycle arrest, cell senescence, and apoptosis (a form of programmed cell death); together, these three processes impede cancer development by preventing damaged cells from surviving and/or proliferating. To overcome this tumor suppression mechanism, aspiring cancer cells must deactivate p53 and activate telomere maintenance mechanisms—two of the most common events in human cancer. In addition to cancer, we have learned that age-associated telomere erosion and activation of p53 underlie many age-related changes in the organism.
The importance of telomeres and p53 in driving the intimate link between aging, epithelial cancers, and genome instability was illuminated by our studies in mouse models of telomere dysfunction. Telomerase-negative "mTERC" null mice display premature aging, diminished stress responses, impaired organ renewal and stem cell depletion. p53 null mice do develop tumors, but those tumors typically display relatively benign cytogenetic profiles. However, mTERC and p53 doubly null mice showed increased cancer incidence with a marked shift towards epithelial cancers with complex cytogenetic abnormalities typical of human carcinomas. Therefore, telomere dysfunction, coupled with deactivated p53 checkpoints, enables genome instability and the development and progression of cancer.
This MERIT award project focuses on elucidation of the "wiring" of the p53-dependent telomere checkpoint response. In telomere-dysfunctional mice with intact p53 function, we have identified a profound deficiency in the biogenesis and function of mitochondria (the energy factories of cells). This mitochondrial defect results from at least two p53-directed changes in the cell: repression of PGC1 (a master regulator of mitochondrial biogenesis) and activation of Quaking (an RNA binding protein that may play an important role in mitochondria biogenesis via actions on microRNAs). We hypothesize that mitochondriopathy with associated energy loss is the primary cause of age-related maladies in telomere-dysfunctional mice and may dictate certain metabolic responses in cancer cells. Our objectives will be to genetically assess the telomere-mitochondria link in aging and cancer. We will first employ an inducible telomerase model to assess the regenerative impact of telomerase re-expression on mitochondrial biology and degenerative phenotypes in stem cells and diverse post-mitotic organ systems in aged telomere-dysfunctional mice. Second, we will genetically define the function of PGC1 and Quaking with respect to mitochondrial biology, degenerative aging, stem cell homeostasis, and cancer progression.Given that telomerase expression is reactivated in cancer cells and anti-telomerase therapy is a major focus of oncology drug development, we propose to validate the principle of telomerase extinction as an anti-cancer therapy. We also propose to define potential resistance mechanisms to anti-telomerase therapy at the genomic and metabolic levels, using our inducible telomerase animal model. It is expected that the identification of these therapy-resistance mechanisms should lead to new drugs that block the resistance mechanisms and may thereby synergize with anti-telomerase therapy.