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EASTBIO: How do human fungal pathogens remodel their genome to acquire drug resistance?


   College of Medicine and Veterinary Medicine

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  Dr Vasso Makrantoni, Prof Jeyaprakash Arulanandam  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Deanery of Biomedical Sciences: Fungal pathogens are a huge burden on human health, killing almost 2 million people every year. With only 3 classes of anti-fungal drugs available and a sharp increase in resistance seen in clinics, there is an urgent need for developing novel strategies against antifungal resistance. Candida albicans is the most common fungal pathogen, responsible for life-threating infections affecting the blood, heart and brain, with devastating consequences in immunocompromised patients. To invade and colonize human bodies, Candida need to survive under various stresses (acidic environment in the gut, high temperature, drugs). One of the mechanisms they use to respond rapidly to these stresses is aneuploidy (incorrect number of chromosomes). This remarkable genome remodelling enables Candida to adapt in diverse environmental niches, and acquire antifungal drug resistance.

This project aims to uncover how aneuploidy happens when Candida encounters genotoxic stress, caused by commonly-used anti-cancer drugs (Cisplatin, Hydroxyurea) in cancer patients.  It will focus on a key regulator that safeguards chromosome numbers, the cohesin complex. By holding the chromosomes together until their timely separation during cell division, cohesin is central to the chromosome segregation process and the repair of DNA double strand breaks that occur following genotoxic stress. Although most cohesin homologs and their regulators are identifiable in Candida by computational methods, whether their function is conserved and how they contribute to its unparalleled genome remodelling has not yet been studied. Given the high frequency of aneuploidy in Candida upon stress, we postulate that our recently discovered mechanism of cohesin distribution in budding yeast [3,4] is modified in Candida, and alternative, Candida-specific regulators must exist. This project will dissect Candida’s unique cohesin regulation following genotoxic stress and will inform discovery of novel drug targets against antifungal resistance, a major global healthcare challenge.

The specific objectives of the project are:

(i) Assess genome-wide distribution of Candida cohesin in the presence and absence of genotoxic stress by generating a complete ChIP-seq libraries [2] of wild-type, mutant-cohesin strains, and Candida clinical bloodstream isolates to correlate altered cohesin function with increased aneuploidy in Candida-infected patients.

(ii) Determine whether this aneuploidy leads to antifungal drug resistance by monitoring individual, fluorescently-labelled chromosomes (microfluidics) following genotoxic stress, and assess the increase in the pathogen’s virulence when these aneuploid strains are introduced in the worm-based model, C. elegans, to ‘mimic’ host infection.

(iii) Dissect the molecular mechanism that regulates genome plasticity, by employing structural/functional analysis and computational modelling of key cohesin components.  Candida structures will be compared to that from budding yeast to reveal the evolutionary trajectory and selective pressures experienced by common genes [1].

Training outcomes: This is an interdisciplinary project at the interface between genetics, structural biology, computational modelling and bioinformatics. Skills that will be developed include sophisticated yeast genetics (CRISPR-Cas9), structural biology (crystal trials)  and biochemistry, microscopy and genomics (ChIP-seq). Central to this project is training in Bioinformatics for ChIP-Seq data analysis, and structural analysis (PyMOL, Chimera, ColabFold). The student will be well supported by a supervisory team with complementary expertise and competencies, and a friendly and collaborative environment. Most importantly, at the end of this project the student will have all of the necessary skills to seamlessly transition between biological, clinical, and computational elements of biomedical science.


Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership (DTP) http://www.eastscotbiodtp.ac.uk/how-apply-0.
EASTBIO Application and Reference Forms can be downloaded via http://www.eastscotbiodtp.ac.uk/how-apply-0
Please send your completed EASTBIO Application Form along with a copy of your academic transcripts to [Email Address Removed]
You should also ensure that two references have been send to [Email Address Removed] by the deadline using the EASTBIO Reference Form.

References

[1]. Hsieh YYP., Makrantoni V., Robertson D., Marston AL., Murray AW. (2020). Evolutionary repair: changes in multiple functional modules allow meiotic cohesin to support mitosis. PLoS Biol; Mar 10;18:e3000635.
[2]. Makrantoni V., and Marston AL. (2019). Analysis of the chromosomal localization of yeast SMC complexes by chromatin immunoprecipitation. Methods in Mol. Biology; 119-38.
[3]. Hinshaw S*., Makrantoni V*., Harrison SC., Marston AL. (2017). The Kinetochore Receptor for the Cohesin loading complex. Cell; 171, 72-84. (* equal contribution)
[4]. Hinshaw S., Makrantoni V., Kerr A., Marston AL., Harrison SC. (2015). Structural evidence for Scc4-dependent localization of cohesin. eLife; doi: 10.7554/eLife.06057.

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