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.
My group is interested in studying the mechanism by which telomeres are maintained. Recently, we determined the cryo-EM structure of human telomerase, a large RNA-protein complex that maintains telomeres by synthesizing the 3’ telomeric repeats at chromosome ends. This opens many opportunities for further study of telomere maintenance.
This PhD project will focus on biochemical, structural and functional analyses of large protein-nucleic acid complexes involved in telomere maintenance. The successful candidate will have the opportunity to acquire experience in mammalian cell culture, in vitro biochemical reconstitution/assays, biophysical analyses, cutting-edge structural biology (with a focus on cryo-EM and X-ray crystallography) and genome editing in mammalian cells. The work will contribute to our understanding of how telomeres are maintained and the molecular basis of telomere dysfunction in human patients. Ultimately, it will aid telomere-based drug design against cancer and aging. The LMB has world-class facilities and provides a great working environment. Enquiries to discuss details of the project are highly encouraged.
Arnoult N & Karlseder J. (2015)
Complex interactions between the DNA-damage response and mammalian telomeres.
Nat. Struct. Mol. Biol. 22, 859-866.
Shay, JW. (2016)
Role of Telomeres and Telomerase in Aging and Cancer.
Cancer Discov 6, 584-593.
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.
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).