Telomeres, mesenchymal stem cells and ALT
Telomeres are essential for capping linear chromosomes and preventing double-strand-break repair by homology dependent recombination (HDR) or non-homologous end joining (NHEJ). In normal cells replication driven telomere erosion results in DNA damage signalling and cellular senescence. Failure to senesce at this checkpoint leads to further cell divisions until crisis, when telomere:telomere fusions are formed by NHEJ. Cells at crisis show a high level of genome instability that usually results in cell death. Surviving cells may be neoplastic but must activate a telomere maintenance mechanism (TMM) to continue proliferation.
Alternative Lengthening of Telomeres (ALT) is a recombination-based mechanism that involves strand invasion by the telomere that is to be lengthened and copying from another telomere, a sister telomere or from extra-chromosomal (TTAGGG)n DNA. ALT is activated in about 15% of cancers overall but a higher percentage of some sarcomas and brain cancers. The reason why cancers activate ALT rather than telomerase is unclear, though many ALT+ tumours arise in mesenchymal tissues. Currently a handful of proteins that are required for ALT are known and a larger number of proteins that have been associated with ALT have been identified. In addition, the chromatin-remodelling gene ATRX, with its partner DAXX, that deposit the H3.3 histone variant at pericentric regions and telomeres are suppressors of ALT. Paradoxically, ALT+ cell lines are thought to suppress NHEJ at telomeres but allow telomere lengthening by a mechanism that shares features of HDR repair. With a better understanding of the ALT mechanism and its regulation, it might be possible to induce cell death in ALT+ cancer cells.
The aims of this project are (1) to use gene-editing tools to mutate selected genes to elucidate their role in ALT and (2) to investigate telomeres and associated proteins in human mesenchymal stem cells to explore why sarcomas are more likely to activate ALT.
For other information about Royle’s lab see: http://www2.le.ac.uk/departments/genetics/people/royle/research
Applicants should expect to hold a 1st or 2.1 BSc in a relevant field by September 2016. Those holding a 2.2 degree plus a Master’s degree or >3 years relevant post-graduate experience may be eligible. Candidates with degrees from abroad may be eligible if their qualifications are deemed equivalent.
Please contact Dr Royle for more information or advice about the application process.
We are an equal opportunities employer and particularly welcome applications for Ph.D. places from women, minority ethnic and other under-represented groups.
This is one of 11 projects available for TWO 3 year-funded studentships to start 26 September 2016 in the Department of Genetics.
The studentships, jointly financed by the Department and the College of Medicine, Biological Sciences and Psychology, are open to Home/EU students and offered at the standard RCUK rate (http://www.rcuk.ac.uk/media/news/160125/).
Application deadline: midday 29th April 2016
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