About the Project
In humans, mutations in the RECQ genes, Bloom’s syndrome helicase (BLM) and Werner’s helicase (WRN) are associated with premature ageing and early onset of cancer1. RECQs are conserved throughout eukaryotes and repair DNA by homologous recombination. In Arabidopsis thaliana, the duplicated RECQ4a/RECQ4b genes are the BLM orthologues2 and function redundantly as anti-recombinases during meiosis and by mutating these genes increased COs ~6.2-fold3. A WRN ortholog is not present in Arabidopsis, but we have recently identified one in wheat (RECQ7)4, as well as the BLM ortholog, RECQ4. We have determined that RECQ7 is a pro-CO factor, and RECQ4 is an anti-CO factor, so the two proteins may act antagonistically in processing DNA recombination intermediates down different repair pathways. We have generated knockout mutants of RECQ4 as well as wheat RECQ7 overexpression lines tagged with fluorescent proteins. The mutants and overexpressing lines require analysis as well as determining the mechanism behind altered CO patterns. We will use state-of-the-art super-resolution fluorescence microscopy in conjunction with immunolocalisation and a panel of antibodies developed in the lab that target specific proteins in the CO pathway. Using this approach we will be able to determine the spatio-temporal dynamics of recombination protein loading on meiotic chromosomes. We will also utilise a genomic approach to monitor CO frequency and distribution either through molecular markers or by whole genome skim-sequencing. As part of the training and to gain a fundamental insight into the function of the RECQ helicases, budding yeast will be employed as a model organism to determine the effect on recombination of RECQ4 and RECQ7 across two different kingdoms. Budding yeast possesses a RECQ4 orthlog (SGS1), but not a RECQ7 ortholog, similarly to Arabidopsis, which may reflect genome size, chromosome structure or chromatin environment. There are three outstanding questions that will be investigated in this PhD project:
Q1. How does RECQ7 function as a pro-recombinase in homologous DNA repair in wheat?
Q2. Does RECQ4 act as an anti-recombinase during meiosis in wheat?
Q3. Can we determine an antagonistic mechanism of action between RECQ4 and RECQ7 using both wheat and budding yeast?
The project will be directly translated into crops as well as providing a fundamental knowledge on homologous DNA repair mechanisms in eukaryotes. You will be trained in all modern techniques in an active research lab, with the opportunity for training in external collaborative labs.
BBSRC Strategic Research Priority: Sustainable Agriculture and Food: Plant and Crop Science
Techniques that will be undertaken during the project:
Fluorescence microscopy (widefield and confocal)
Crossing wheat genotypes
Yeast tetrad analysis
This studentship provides the opportunity to make a substantial contribution to fundamental science that can also potentially be translated into wheat and barley during the duration of the project.
UK/EU applicants only.
Applicants are required to hold/or expect to obtain a UK Bachelor Degree 2:1 or better in a relevant subject.
The University of Leicester English language requirements apply where applicable: https://le.ac.uk/study/research-degrees/entry-reqs/eng-lang-reqs/ielts-65
To apply for the PhD please refer to the guidelines and use the application link at https://le.ac.uk/study/research-degrees/funded-opportunities/bbsrc-mibtp
Please also submit your MIBTP notification form at https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/
Project enquiries: Dr James Higgins ([Email Address Removed])
Funding enquiries: [Email Address Removed]
Application enquiries: [Email Address Removed]
UK/EU fees and stipend at UKRI rates. For 2021 this will be £15,285 pa
2. Hartung et al., Proc Natl Acad Sci USA, vol. 104, no. 47, pp. 18836–18841, 2007.
3. Seguéla-Arnaud et al., Proc Natl Acad Sci USA, vol. 112, no. 15, pp. 4713–4718. 2015.
4. Gardiner et al., Genome Biol, vol. 20, no. 1, p. 69. 2019.
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