Mechanistic studies of mammalian telomere maintenance

Telomeres cap the ends of eukaryotic chromosomes and are essential for maintaining chromosome stability, cell viability and setting long-term proliferative capacity. Telomere dysfunction has been implicated in cancer and premature aging. Our work aims to understand how mammalian cells overcome the problems of shortened telomere length caused by incomplete genome replication, and chromosome ends being subject to fusion and repair.

These problems directly impact telomere maintenance and chromosome integrity, and are ameliorated by two large complexes, telomerase and shelterin, respectively, in mammalian cells. We will use a combination of in vitro biochemical reconstitution, cryo-electron microscopy (cryo-EM) and functional studies in vivo to dissect the molecular mechanisms of these complexes. We will also take advantage of recent developments in cryo-electron tomography (cryo-ET) to investigate high-order telomere structures and their role in telomere maintenance. The proposed research will provide detailed insights into these two fundamental problems of telomere maintenance in mammalian cells, and explain how telomere dysfunction gives rise to human diseases.