About the Project
Interested individuals must follow Steps 1, 2 and 3 at this link on how to apply
http://www.ed.ac.uk/biology/prospective-students/postgraduate/pgr/how-to-apply
Telomeres are the ends of eukaryotic chromosomes which are maintained by the enzyme telomerase. Telomerase activity keeps telomeres long, and long telomeres make chromosome ends distinct from DNA breaks. When telomeres are short, this distinction is lost and chromosome ends fuse and recombine, resulting in genetic instability and cancer. Telomerase insufficiency (TI) caused by mutations in human telomerase genes leads to telomeropathies, developmental syndromes characterised by accelerated telomere shortening and increased risk of cancer.
Most eukaryotes, including commonly used model systems (worms, fish, frogs, mice, etc.) express telomerase constitutively. In contrast, human telomerase expression is downregulated during development and the remaining telomerase is not sufficient to compensate for telomere attrition during replication, resulting in progressive telomere shortening. Replicative senescence is a clock which eventually halts the cell cycle in response to critically short telomeres. On one hand, the developmentally programmed TI contributes to cell ageing but on the other – it inhibits unlimited proliferation and cancer. Therefore, understanding how cells deal with TI has important implications for elucidating molecular mechanisms of normal human ageing and disease.
The goal of the project is to understand telomere dynamics in cells with TI/critically short telomeres and how they affect genome integrity. We have recently discovered naturally occurring TI in yeast, the only known example other than the developmentally programmed TI in larger animals (Millet et al., 2015). This discovery has opened a unique and unforeseen opportunity to study TI in a much simpler and genetically tractable setting. We will make use of a unique microfluidics device, developed by the Swain lab, to track individual cells for a number of consecutive generations in order to analyse how different levels of TI affect cell cycle length and progression through the S/G2 stages of the cell cycle when telomerase is active. Combined with fluorescent microscopy to visualise GFP/YFP/RFP-tagged proteins, this approach will allow us to monitor the progress of repair of critically short telomeres.
We are looking for applicants with good analytical thinking, knowledge of cell and molecular biology, who are interested in genome maintenance mechanisms and enthusiastic about scientific research. The student will gain expertise in genome stability mechanisms, DNA repair and cancer. The experimental part of the project will provide training in yeast genetics and a wide range of molecular biological techniques (microscopy, PCR and qPCR, cloning, Southern, Northern, and Western blotting, protein and chromatin immunoprecipitation, genomics, etc.) as well as basic bioinformatics skills. The student will be trained to use the required experimental techniques and also will develop scientific data analysis and presentation skills by participating in lab meetings and journal club sessions, as well as by attending Institute seminars, the PhD program courses, and research conferences. Through weekly meetings with the supervisor, s/he will learn designing experiments, interpreting the results and exploiting novel research directions to navigate towards becoming an independent researcher.
Further Information
This is a collaboration project between the Makovets (telomere biology) and Swain (single-cell analyses using microfluidics) labs.
Informal enquiries can be made by contacting Dr. Sveta Makovets by email: [Email Address Removed]
References
1. Millet, C., Ausiannikava, D., Le Bihan, T., Granneman, S. & Makovets, S. Cell populations can use aneuploidy to survive telomerase insufficiency. Nature Communications 6, 8664, (2015).
2. Xu Z, Fallet E, Paoletti C, Fehrmann S, Charvin G, Teixeira MT. Two routes to senescence revealed by real-time analysis of telomerase-negative single lineages. Nature Communications 6, 7680, (2015).