Supervisors:
Dr Alexander Lorenz - Institute of Medical Sciences University of Aberdeen - [Email Address Removed]
Professor Anne Donaldson - Institute of Medical Sciences University of Aberdeen - [Email Address Removed]
Professor Adele Marston - Wellcome Centre for Cell Biology University of Edinburgh - [Email Address Removed]
Dr Bin Hu - Institute of Medical Sciences University of Aberdeen - [Email Address Removed]
Project Description for Find-A-PhD Advert (max 400 words). This will be the text that is advertised to prospective students:
The mitotic cell cycle (DNA replication followed by cell division) produces two identical daughter cells from a single precursor. Its accuracy is of the utmost importance to maintain cell health, indeed, cell cycle dysregulation can cause cancer. The cell cycle phase during which DNA is replicated is called S-phase.
Meiosis is the specialised cell division that produces gametes. Intriguingly, despite many similarities in control mechanisms, the meiotic cell cycle proceeds more slowly than the mitotic one. The substantial extension of pre-meiotic S-phase is due to reduced efficiency in origin firing and slow replication fork progression, but how this is controlled remains unclear.
Rif1 is a key regulator of mitotic S-phase, which ensures the orderly progression of S-phase. However, the role of Rif1 in controlling meiotic DNA replication is unknown. This project will exploit the awesome power of yeast genetics to examine Rif1’s function(s) during meiosis. Two unrelated yeast species, Saccharomyces cerevisiae and Schizosaccharomyces pombe, will be examined to establish whether Rif1 meiotic roles are evolutionarily conserved.
1) How does Rif1 affect origin usage during pre-meiotic S-phase?
Progression through pre-meiotic S-phase in wildtype and rif1 mutant cells will be analysed to determine differences in origin usage in S. cerevisiae and Sz. pombe, using approaches of genome-wide profiling and single-molecule nanopore-sequencing-based analysis of DNA replication. Comparison with known effects on mitotic S-phase will reveal whether Rif1 works similarly during pre-meiotic S-phase. For example, in mitotic S-phase Rif1 strongly delays the replication of telomere regions. Does Rif1 also delay telomere replication in premeiotic S-phase?
2) How is meiotic recombination affected by Rif1, and does Rif1 control recombination directly, or indirectly as a consequence of dysregulated pre-meiotic S-phase?
We will investigate the effects of Rif1 deficiencies on meiotic recombination. Using separation-of-function mutants and tags that allow inducible degradation, we will test whether effects are due to a direct effect of Rif1 on meiotic recombination, or else a consequence of changes to origin initiation and replication dynamics.
3) Is meiotic chromosome pairing and segregation altered in the absence of Rif1?
Meiotic chromosome pairing depends on recombination. Faithful chromosome segregation requires recombination and the loading of the cohesin complex. Both recombination and cohesin loading sites tend to be close to efficiently activated DNA replication origins. We will test whether the absence of Rif1 causes changes in recombination and cohesin distribution, and how this affects the viability of gametes.
Overall, this project will employ state-of-the-art genetics and cell biological techniques to elucidate the meiotic role(s) of Rif1, a key regulator of DNA replication and repair.
Application Procedure:
Please visit this page for full application information: http://www.eastscotbiodtp.ac.uk/how-apply-0
Please send your completed EASTBIO application form, along with academic transcripts to Alison Innes at [Email Address Removed]
Two references should be provided by the deadline using the EASTBIO reference form.
Please advise your referees to return the reference form to [Email Address Removed]
Unfortunately due to workload constraints, we cannot consider incomplete applications
Continue with Facebook
