How does the nucleolus safeguard ribosome production during meiosis?

Sexual reproduction relies on accurate meiosis, the unique cell division process which creates sperm and egg. All meiotic cells must maintain ribosomal (r)DNA integrity to avoid infertility, miscarriages and birth defects, but it is unclear how this is accomplished in mammalian cells or why the process becomes more error-prone at a later age. Importantly, the ever-increasing average age of first-time parents in developed countries calls for research into these questions to empower the identification of new targets for clinical intervention.

To allow for fertility and occurrence of novel traits, meiosis facilitates large-scale genome rearrangements during gametogenesis. This is achieved by the meiosis-specific synaptonemal complex (SC), which aligns homologous chromosomes. However, highly repetitive DNA elements like ribosomal (r)RNA genes, which are arranged in arrays with hundreds of rDNA units in tandem, pose a substantial risk to genome stability during meiosis since they can undergo nonallelic exchanges.

Unsupervised rDNA recombination during meiosis would result in faulty ribosomes compromising protein synthesis and consequently fertility. Initiated by rDNA transcription in the nucleolus, ribosome assembly follows an intricate and energy-consuming pathway involving hundreds of factors, including pre-ribosomal RNA cleavage enzymes that enable stepwise processing of the mature rRNAs from a precursor transcript. Interestingly, one of these enzymes, the RNA exosome associated exonuclease EXOSC10/Rrp6, was recently demonstrated to be essential for spermatogenesis and oocyte maturation, suggesting surveillance of ribosome production at the onset of meiosis to avoid mistakes and therefore energy waste, but the roles of other ribosome assembly factors have not been explored.

This PhD project based at Newcastle with a placement in Liverpool will involve a unique breath of training in complementary approaches (biochemistry, cell biology, human cell culture, mouse models, proteomic and state-of-the-art imaging techniques) to investigate the mechanisms by which mammalian cells may regulate ribosome production to protect their rDNA loci from nonallelic exchanges during meiosis.

This project is suited to students who need flexible working arrangements, and we welcome applications from minority backgrounds. A broad range of inter-disciplinary approaches will encourage innovative thinking and develop diverse technical expertise. Furthermore, this multi-disciplinary training will give the student a broad range of skills allowing them a wide choice of career options, both within and outside of academia, after the PhD.

For more information see https://www.ncl.ac.uk/medical-sciences/people/profile/claudiaschneider; https://www.mcclurglab.com; Twitter: @CSchneiderNCL; @CBCC_NCL; @UrszulaMcclurg.

Please contact [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);

·      a covering letter – clearly stating your first choice project, and optionally 2^nd ranked project, as well as 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(s) and at the selected University;

·      copies of your relevant undergraduate degree transcripts and certificates;

·      a copy of your IELTS or TOEFL English language certificate (where required);

·      a copy of your passport (photo page).

A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.nld-dtp.org.uk/how-apply. Applications not meeting these criteria may be rejected.

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

The deadline for all applications is 12noon on Monday 9^th January 2023.