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Exploring fungal-specific aspects of ribosome production to find new ways to protect global food security and human health

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  • Full or part time
    Dr C Schneider
    Prof M X Caddick
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Fungal contamination leads to reduced harvest and post-harvest food spoilage and accounts for the loss of 10-20% of food production worldwide. Food loss is often due to contamination with mycotoxins such as aflatoxins, which are carcinogens and can cause severe liver damage. The rising threat of fungicide resistance further calls for research into essential cellular pathways to find new targets for drugs against plant and animal pathogenic fungi. This PhD project will explore fungal-specific aspects of ribosome production as new targets for anti-fungal drug discovery.

The multi-subunit endoribonuclease RNase MRP is conserved in all eukaryotes and often mutated in human disease (e.g. cartilage-hair hypoplasia), but its catalytic mechanism is not fully understood. While RNase MRP contributes to cell cycle regulation, its main role is in the production of ribosomes, the large RNA-protein machines that synthesise all cellular proteins. Ribosome production is essential for all cells and directly determines their proliferative rate.

Key events in ribosomal RNA (rRNA) maturation, a pathway best characterised in budding yeast (Saccharomyces cerevisiae), are cleavages, for example catalysed by RNase MRP, that release the mature rRNAs from a precursor transcript. Orthologues of most yeast ribosome biogenesis factors are present or predicted in all eukaryotes including fungi, but functional studies in models for pathogenic fungi (e.g. Aspergillus nidulans) are in their infancy. Importantly, fungal RNase MRP contains two essential protein components that are not present in multicellular organisms and could therefore be new targets for anti-fungal drugs.

In this DTP3 partnership PhD project with the main base at Newcastle and a placement in Liverpool, you will study RNase MRP and its roles in pre-ribosomal RNA cleavage and cell cycle regulation in budding yeast, Aspergillus nidulans and human cells, aiming to identify chemical compounds that specifically inhibit fungal, but not human RNase MRP.

You will learn genetic, cell biology, biochemistry and structural biology techniques to characterise RNase MRP in three different biological systems. This will include affinity-purification of fungal and human RNase MRP complexes to compare their catalytic activities, 3D-structures, and sensitivity to chemical compounds. In parallel, you will use in vivo systems to characterise RNase MRP and the importance of its fungal-specific components.

You will be part of the flourishing postgraduate culture at Newcastle/Liverpool Universities and you will be able to present your research at national/international conferences.

If you are interested in this PhD, please contact Dr Claudia Schneider ([Email Address Removed])
for an informal chat about the project.

HOW TO APPLY

Applications should be made by emailing [Email Address Removed] with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project and at the selected University. Applications not meeting these criteria will be rejected.

In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Please note that the closing date for applications is Monday 18th May at 12noon.

Funding Notes

This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

(2019) Interactions and activities of factors involved in the late stages of human 18S rRNA maturation. RNA Biology, doi: 10.1080/15476286.2018.1564467.

(2018) Turnover of aberrant pre-40S pre-ribosomal particles is initiated by a novel endonucleolytic decay pathway. Nucleic Acids Res. Feb 22. doi: 10.1093/nar/gky116.

(2017) The ribosome biogenesis factor yUtp23/hUTP23 coordinates key interactions in the yeast and human pre-40S particle and hUTP23 contains an essential PIN domain. Nucleic Acids Res. 45(8):4796-4809. doi: 10.1093/nar/gkw1344.

(2016) The PIN domain endonuclease Utp24 cleaves pre-ribosomal RNA at two coupled sites in yeast and humans. Nucleic Acids Res. 44(11):5399-409.

(2012) Transcriptome-wide Analysis of Exosome Targets. Mol. Cell 48(3):422-33.

(2012) Proofreading of pre-40S ribosome maturation by a translation initiation factor and 60S subunits. Nat Struct Mol Biol. 19(8):744-53.

(2009) RNA helicase Prp43 and its co-factor Pfa1 promote 20S to 18S rRNA processing catalyzed by the endonuclease Nob1. J Biol Chem. 284, 35079-91.

(2016) Current challenges of research on filamentous fungi in relation to human welfare and a sustainable bio‑economy: a white paper. Fungal Biol Biotechnol 3: 6.

(2012) mRNA 3' tagging is induced by nonsense mediated decay and promotes ribosome dissociation. Mol. Cell. Biol. vol 32: pp 2585-2595.

(2010). CUCU modification of mRNA promotes decapping and transcript degradation in Aspergillus nidulans. Mol. Cell. Biol. vol30: pp 460-469.

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