Linear eukaryotic chromosome ends consist of G-rich sequences (TTAGGG in humans) bound by specific protein factors to form large nucleoprotein structures called telomeres. Telomeres play essential roles in preventing chromosomal ends from being recognized as DNA damage breaks and thus maintain genome integrity. Telomeres, however, shorten with each round of cell division due to the end-replication problem. Cells with critically short telomeres undergo growth arrest and apoptosis due to the genomic instability. Failures to maintain telomeres properly have been demonstrated to result in a number of human diseases, aging and cancers.
Cancers, stem cells and germline cells upregulate telomerase, a large protein-RNA complex which synthesizes telomeric repeats to compensate for telomere loss caused by the end-replication problem. These cells can thus maintain long-term proliferation . Telomerase is, therefore, often regarded as the ”immortality enzyme” and is an attractive drug target against cancer and aging. We recently obtained the cryo-EM structure of human telomerase at medium resolution. The structure not only confirmed the composition of human telomerase but also provides unprecedented architecture insight into how the 11 subunits of telomerase are organized. It opens up opportunities to study aspects of telomerase regulation at telomeres.
Our lab uses structural biology to investigate telomere biology in yeast and human. We develop biochemical methods to obtain protein-nucleic acid complexes involved in telomere maintenance pathways both from endogenous sources and by overexpression methods. We use a range of biochemical and biophysical assays for complex characterization, followed by structural studies by various techniques including cryo-EM, X-ray crystallography and NMR. We are also planning to use cryo-ET in the future. In addition, we also perform in vivo studies in yeast and model human cell lines to support our structural data. Our structural work can be ultimately used for therapeutic studies targeting cancers and aging.