Telomeres and Telomerase

Research Focus 1: Telomeres and Telomerase 

A fundamental challenge in cancer and aging research is the lack of appropriate model systems that recapitulate the small physiological changes that compound over the human lifespan to lead to pathologies. A particularly fascinating subject is the tenuous balance inherent in the telomere maintenance pathway: slight aberrant activation is strongly linked to cancer while a relatively small deficiency results in premature stem cell aging and tissue failure. Our research focuses on developing genetically accurate human model systems that can recapitulate these pathologic defects in the telomerase pathway as well as the tools to gain a mechanistic understanding of the molecular changes that drive them. Moreover, we apply the insights and technologies developed during our studies of telomere biology towards the broader and often synergistic goal of investigating aspects of human stem cell biology, tissue physiology and pathology that are specific to humans and difficult to model with conventional model organisms.

Our goal is to shed light on the key functions of telomeres and telomerase in tissue homeostasis, tumorigenesis and aging.  Telomeres are the repetitive DNA sequences at the end of linear eukaryotic chromosomes that allow a cell to distinguish the natural chromosome end from aberrant DNA breaks.  Telomeric DNA repeats can be generated de novo by the enzyme telomerase thereby providing a compensatory mechanism that counteracts terminal sequence loss caused by the end replication problem.  As a result, telomeres and telomerase are essential to genomic integrity and their disruption is associated with cancer and aging.   The use of genetic mouse models has been a powerful way to gain insight into the fundamental mechanisms of how the telomere evades recognition by the DNA-damage machinery, the consequences of telomerase loss, and how the single stranded telomeric overhang is established.  However, telomere shortening naturally occurs only in human somatic cells, but not in mouse cells. This telomere shortening, which functions as a tumor suppressor mechanism by limiting the replicative potential of human cells, is the result of selective silencing of telomerase expression in human cells upon their differentiation.  Notably, this process is reversed and telomerase reactivated in about 90% of all human tumors after which telomerase expression becomes essential for their proliferation.