Coventry University Featured PhD Programmes
University of Oxford Featured PhD Programmes
Sheffield Hallam University Featured PhD Programmes
University of Leeds Featured PhD Programmes
Cardiff University Featured PhD Programmes

EASTBIO: Does Rif1 regulate meiotic DNA replication and recombination?

  • Full or part time
    Dr A Lorenz
    Prof A Donaldson
    Prof A Marston
  • Application Deadline
    Sunday, January 05, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

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/

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, 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 initiation and DNA repair, 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?
For both S. cerevisiae and Sz. pombe, genome-wide profiling of progression through pre-meiotic S-phase in wildtype and rif1 mutant cells will determine differences in origin usage. 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 the recombination processes, 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 cohesion loading, 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 and CV to Alison McLeod at . Two references should be provided by the deadline using the EASTBIO reference form. Please advise your referees to return the reference form to .

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership. This opportunity is only open to UK nationals (or EU students who have been resident in the UK for 3+ years immediately prior to the programme start date) due to restrictions imposed by the funding body. Queries on eligibility? Email Alison McLeod ().

Candidates should have (or expect to achieve) a minimum of a First Class Honours degree in a relevant subject. Applicants with a minimum of a 2:1 Honours degree may be considered provided they have a Distinction at Masters level.

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



FindAPhD. Copyright 2005-2019
All rights reserved.