The ends of linear eukaryotic chromosomes are typically composed of tandem G-rich repeats, which play a crucial role in attracting telomeric protein factors to assemble large nucleoprotein structures known as telomeres. These telomeres are vital for safeguarding chromosome ends from being misidentified as DNA breaks, thereby preserving genome integrity. Dysfunction in telomeres is closely associated with cancer and aging-related diseases.
As a result of the end-replication problem, telomeres progressively shorten with each round of cell division. To counterbalance this telomere attrition, the telomerase ribonucleoprotein (RNP) complex adds telomeric repeats to chromosome ends. Notably, telomerase has evolved to exhibit significant diversity across eukaryotes, as evidenced by the varied composition of telomerase complexes in three commonly studied phylogenetic groups: ciliates, vertebrates, and fungi. In recent years, my group has extensively characterized human telomerase using biochemical and structural approaches, and structures of ciliate telomerase have also been elucidated. However, the structural characterization of yeast telomerase remains unexplored.
This PhD project aims to investigate the biochemical, structural, and functional aspects of yeast telomerase complexes. The successful candidate will gain experience in yeast cell culture, biochemical reconstitution/isolation of telomerase complexes, biophysical analysis, and advanced structural biology techniques, with a particular emphasis on cryo-electron microscopy (cryoEM) and cryo-electron tomography (cryoET). This research will provide valuable insights into the fascinating evolution of telomerases. The LMB offers world-class facilities and an excellent working environment. Prospective candidates are encouraged to reach out to discuss the project details further.
References
Nguyen, T.H.D., Tam, J., Wu, R.A., Greber, B.J., Toso, D., Nogales, E., Collins, K. (2018)
Cryo-EM structure of substrate-bound human telomerase holoenzyme
Nature 557(7704): 190-195
Nguyen, T.H.D., Collins, K., Nogales, E. (2019)
Telomerase structures and regulation: shedding light on the chromosome end
Curr Opin Struct Biol 55: 185-193
Wellinger, R.J., Zakian, V.A. (2012)
Everything you ever wanted to know about Saccharomyces cerevisiae telomeres: beginning to end
Genetics 191(4): 1073-105
Jiang, J., Wang, Y., Sušac, L., Chan, H., Basu, R., Zhou, Z.H., Feigon, J. (2018)
Structure of Telomerase with Telomeric DNA
Cell 173(5): 1179-1190
Ghanim, G.E., Fountain, A.J., Roon, A.M.v., Rangan, R., Das, R., Collins, K., Nguyen, T.H.D. (2021)
Structure of human telomerase holoenzyme with bound telomeric DNA
Nature 593(7859): 449-453
He, Y., Wang, Y., Liu, B., Helmling, C., Sušac, L., Cheng, R., Zhou, Z.H., Feigon, J. (2021)
Structures of telomerase at several steps of telomere repeat synthesis
Nature 593(7859): 454-459