Research Interests – The Challenges and Solutions at TELOMERES

The preservation and faithful transmission of genomes is fundamental to life. The partition of eukaryotic genomes into linear chromosomes posed two profound challenges to genome preservation and transmission. The first is for the cells to distinguish natural chromosome ends, or telomeres, from abnormal double strand breaks—in order to leave the natural ends intact, but repair the aberrant breaks. In addition, because of a fundamental quirk of DNA polymerase, a small amount of DNA is lost from telomeres with each round of genome replication, making it imperative for an organism to devise compensatory mechanisms. To overcome the two challenges at telomeres, eukaryotic organisms have managed to (1) coat chromosome ends with special proteins to stabilize the termini, and (2) invent elaborate molecular machines to add telomeric DNA (e.g., telomerase). When these telomere proteins and machines malfunction, there is heightened risk for genomic instability and related diseases such as cancer and aging. 

We are intrigued by many unanswered questions surrounding telomeres: How do the machines that synthesize telomeric DNA work and how are they regulated?  What happens to these machines in disease states, especially in cancers? Which protein factors at telomeres are valuable therapeutic targets? How do different organisms evolve distinct telomere structures and telomere synthesizing machines? 

We investigate these questions using both unicellular model organisms and cancer cells. Typically for an interesting issue, we first identify a model system that shares essential features of the human telomere machinery under investigation, make mechanistic discoveries using the model system, and then apply the insights to the analysis of human factors.

Projects

1) The mechanism and regulation of telomerase.