Molecular mechanism of telomere maintenanceGroup Leader Page
Linear eukaryotic chromosomes are capped with telomeres, which protect chromosomes against degradation and inter-chromosomal fusion and thus are essential for maintaining genome integrity. Due to the end-replication problem inherent to linear chromosomes, telomeres are progressively shortened over multiple cell divisions. Critically short telomeres result in proliferative senescence and cell death. Telomere dysfunction is strongly linked to cancers and premature aging diseases such as dyskeratosis congenita, aplastic anemia, and pulmonary fibrosis. We determined the cryo-EM structure of human telomerase, a large ribonucleoprotein (RNP) complex that maintains telomeres by synthesizing the 3’ telomeric repeats at chromosome ends.
Telomeres, telomeric proteins and telomerase are highly divergent in compositions and structures in commonly studied groups of eukaryotes such as ciliates, yeast and vertebrates. This is evident in the differences between the structures of the ciliate Tetrahymena and human telomerase. We are interested in studying the mechanisms by which telomeres are maintained and the evolution of telomerase RNP and telomeres across different eukaryotes.
This PhD project will focus on biochemical, structural and functional analyses of large protein-nucleic acid complexes involved in telomere maintenance in the well-studied model organism Saccharomyces cerevisiae. The successful candidate will have the opportunity to acquire experience in yeast culture, biochemical reconstitution and purification from yeast, in vitro biochemical assays, biophysical analyses, cutting-edge structural biology (with a focus on cryo-EM and X-ray crystallography) and yeast genetics. Together with the previous work on the ciliate and human systems, the work will provide important insight into the divergent evolution of telomerase and telomeres. The LMB has world-class facilities and provides a great working environment. Enquiries to discuss details of the project are highly encouraged.
de Lange, T. (2018)
Shelterin-Mediated Telomere Protection.
Annu Rev Genet 52, 223-247.
Jiang, J., Wang, Y., Sušac, L., Chan, H., Basu, R., Zhou, Z. H. and Feigon, J. (2018)
Structure of Telomerase with Telomeric DNA.
Cell 173, 1179-1190.
Nguyen THD, Tam J, Wu RA, Greber BG, Toso D, Nogales E, Collins K. (2018)
Cryo-EM structure of substrate-bound human telomerase holoenzyme.
Nature 557, 190-195.
Wu, R. A., Upton, H. E., Vogan, J. M. and Collins, K. (2017)
Telomerase Mechanism of Telomere Synthesis.
Annu Rev Biochem
Wellinger, R. J. and Zakian, V. A. (2012)
Everything you ever wanted to know about Saccharomyces cerevisiae telomeres: beginning to end.
Genetics 191, 1073-1105.
Nguyen THD, Collins K, Nogales E. (2019)
Telomerase structures and regulation: shedding light on the chromosomal end.
Curr. Opin. Struct. Biol. 55, 185-193 (2019).