Molecular mechanism of telomere maintenance and the roles of telomeres in human diseases
The ends of linear eukaryotic chromosomes are capped telomeres, an array of long telomeric repeat tracts ([TTAGGG]nin human) bound by telomeric protein factors. Telomeres distinguish natural chromosomal ends from DNA breaks and thereby protect chromosomes against degradation and interchromosomal fusion. Each cell division results in the loss of a small portion of telomeres as a consequence of incomplete genome replication. Critically short telomeres lose their end-protection capability, resulting in genome instability, proliferative senescence or cell death. Therefore, telomere length is often regarded as a “cellular aging clock” and telomere maintenance is essential for genome integrity. Telomere dysfunction has been linked to cancers and premature aging syndromes such as dyskeratosis congenita, aplastic anemia, and pulmonary fibrosis in human patients.
We developed biochemical methods to reconstitute human telomerase holoenzyme, a large ribonucleoprotein that compensates for telomere shortening by synthesizing the 3’ telomeric DNA repeats, and determined its cryo-EM structure at medium resolution. The structure settled the longstanding question regarding its composition and gave unprecedented insight into its assembly.
We are studying telomerase regulation at telomeres and other processes involved in telomere maintenance beyond telomerase. We employ an integrated structural biology approach with a focus on biochemistry, cryo-electron microscopy and in vivo studies in mammalian cells. Ultimately, our aim is to uncover how mutations in human patients result in telomere dysfunction, which will be essential for telomere-based therapeutics.
Kelly will join the LMB in August 2019.