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Elucidating eukaryotic Topoisomerase III activity in homologous recombination


School of Life Sciences

, Dr William Gittens Wednesday, June 30, 2021 Funded PhD Project (UK Students Only)

About the Project

DNA topoisomerases are a family of enzymes that mediate topological transformations of genomic DNA across all domains of life—facilitating transcription, replication, the dissolution of homologous recombination intermediates, and the segregation of chromosomes in mitosis and meiosis. DNA topoisomerases perform this function by creating transient DNA breaks, allowing relief of superhelical stress or the removal of intertwines and catenanes, prior to resealing of the DNA phosphate backbone. In all cases, this mechanism proceeds via formation of a covalent topoisomerase-DNA intermediate, referred to as a covalent complex (CC). 

This PhD project will utilise genome-wide methods to elucidate the role and activity of Topoisomerase III (Top3) during homologous recombination (HR). 

In budding yeast, Top3 plays diverse roles in several topologically-constrained genomic processes. In particular, vegetative hyper-recombination, and defective sporulation of top3Δ mutants underscore the role of the Top3-Sgs1-Rmi1 (STR) dissolvase complex in the dissolution of HR intermediates generated during DNA repair in mitotic and meiotic cells, to form noncrossover products. However, it is unknown how this role is regulated temporally and spatially, within the genome landscape. 

To discover when and where Top3 acts, and how this is influenced by intrinsic genome organisation, you will use the cutting-edge CC-seq method (developed in-house[1]) to generate genome-wide maps of Top3 activity in budding yeast cells. You will compare Top3 CC-seq signals in meiosis with maps of other topoisomerase activity, and with programmed Spo11-induced DSBs, crossovers, and gene-conversion—thereby revealing mechanistic insights into the spatial relationship between where HR events are initiated and where they are resolved/dissolved. Furthermore, you will aim to reveal whether there are hotspots of Top3-mediated dissolution, and if so, how these relate to structural features of meiotic chromosomes, such as chromatin looping mediated by cohesin, condensin and the meiotic axis proteins. 

You will gain a diverse skill set, including cell biology & genetic manipulation, biochemistry & molecular biology, and bioinformatic & genomic analysis. Working closely with Dr William Gittens and Dr Matt Neale, you will be involved in all aspects of project development, including theoretical research, experimentation & data analysis, and methodology development.

Work Environment:

You will join the Neale Lab at the world-renowned and highly-collaborative Genome Damage and Stability Centre (GDSC), within the University of Sussex School of Life Sciences. This centre hosts seventeen research groups working on complementary aspects of genome stability, providing unparalleled opportunities for scientific discussion, theoretical guidance and technical expertise directly related to the project. The Neale laboratory is focused on understanding fundamental aspects of chromosome structure and DNA repair, particularly in the setting of budding yeast meiosis.

How to apply:

Interested candidates are encouraged to apply early and contact the supervisors directly for more information ( and ).

Please also submit a formal application using the online system at www.sussex.ac.uk/study/phd/apply attaching a CV, degree transcripts and certificates, statement of interest and two academic references.

On the application system select Programme of Study – PhD Genome Stability.

Please ensure you state the project title under funding and include the proposed supervisor’s name where required.

Eligible applicants will hold a 2:1 BSc in a relevant subject, with a keen interest in the project. Ideal candidates will have an MSc or equivalent in Genetics, Biochemistry, Genomics, or a related subject. Candidates for whom English is not their first language will require an IELTS score of 6.5 overall, with not less than 6.0 in any section.


Funding Notes

A Ph.D. studentship (3.5 years) is available from September 2021 under the supervision of Dr Matthew Neale and Dr William H Gittens, Genome Damage and Stability Centre, School of Life Sciences. The project is funded by the University of Sussex and the BBSRC.
This funded position covers Home tuition fees and a stipend at standard UKRI rates for 3.5 years. Applicants with overseas fee status will need to fund the difference between Home and International tuition fees.

References

Gittens, W.H., Johnson, D.J., Allison, R.M. et al. A nucleotide resolution map of Top2-linked DNA breaks in the yeast and human genome. Nat Commun 10, 4846 (2019). https://doi.org/10.1038/s41467-019-12802-5

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