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EASTBIO Does Rif1 regulate meiotic DNA replication and recombination?


School of Medicine, Medical Sciences & Nutrition

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Dr A Lorenz , Prof A Donaldson , Prof A Marston , Dr B Hu No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Supervisors:

Dr Alexander Lorenz (University of Aberdeen)
https://homepages.abdn.ac.uk/a.lorenz/pages/index.html

Professor Anne Donaldson (University of Aberdeen)
https://www.abdn.ac.uk/ims/profiles/a.d.donaldson

Professor Adele Marston (University of Edinburgh)
http://marston.bio.ed.ac.uk/

Dr Bin Hu (University of Aberdeen)
https://www.abdn.ac.uk/ims/research/profiles/bin.hu

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 genome integrity and cell health, as exemplified by cell cycle dysregulation as a hallmark of cancer. The cell cycle phase during which DNA is replicated is called S-phase.
Meiosis is the specialised cell division that produces gametes. Intriguingly, the meiotic cell cycle proceeds more slowly than the mitotic one. The substantial extension of pre-meiotic S-phase has been explained by reduced efficiency in origin firing1,2 and slow replication fork progression (https://doi.org/10.1101/2020.09.23.308874), but how this is controlled remains unclear.
Rif1 is a key regulator of mitotic S-phase, which restrains replication origin initiation to ensure the orderly progression of S-phase. Although it is a conserved regulator of mitotic DNA replication, the effect of Rif1 in controlling meiotic DNA replication has not been studied. This project will exploit the awesome power of yeast genetics to examine functions of Rif1 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?
Genome-wide profiling of progression through pre-meiotic S-phase in wildtype and rif1 mutant cells will determine differences in origin usage in S. cerevisiae and Sz. pombe. Comparison with known effects on mitotic S-phase will reveal whether Rif1’s role in restraining DNA replication initiation also occurs 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?
Recombination assays3 will be used to investigate effects of Rif1 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 largely depends on recombination, and 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.
The successful candidate will be trained in advanced genetics, genomics, and molecular cell biology techniques, including next-generation sequencing, microscopic analysis, and comparative yeast genetics & genomics, exploiting new ways of working to elucidate a fundamental cellular process crucial to cell health and human fertility. This project will deliver novel insight into how pre-meiotic S-phase is regulated and how this affects meiosis and reproductive success.

Application Procedure:

http://www.eastscotbiodtp.ac.uk/how-apply-0

Please send your completed EASTBIO application form, along with academic transcripts to Alison McLeod 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].

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership http://www.eastscotbiodtp.ac.uk/how-apply-0. This opportunity is open to UK and International students and provides funding to cover stipend and UK level tuition (limited funding is available to provide international tuition fees). Please refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria.

Candidates should have (or expect to achieve) a minimum of a 2:1 UK Honours degree, or the equivalent qualifications gained outside the UK, in a relevant subject.

References

1. Blitzblau HG, Chan CS, Hochwagen A, Bell SP. Separation of DNA replication from the assembly of break-competent meiotic chromosomes. PLoS Genet. 2012;8(5):e1002643. doi:10.1371/journal.pgen.1002643
2. Wu PYJ, Nurse P. Replication origin selection regulates the distribution of meiotic recombination. Mol Cell. 2014;53(4):655-662. doi:10.1016/j.molcel.2014.01.022
3. Li D, Roca M, Yuecel R, Lorenz A. Immediate visualization of recombination events and chromosome segregation defects in fission yeast meiosis. Chromosoma. 2019. doi:10.1007/s00412-019-00691-y

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