Where environmental stress tolerance meets biotechnology – understanding Cereblon E3 ubiquitin ligase function during stress responses and targeted protein degradation in plants

• Funding – BBSRC funded 4 year studentship, providing tuition fees, training/research costs and an annual stipend at the UKRI rate, currently £21,80
• Start Date – September 2027
• Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline. 
   

Plants use ubiquitination to regulate cellular function more than any other group of Eukaryotes. As a result, they are excellent candidates for deployment of targeted protein degradation (TPD) approaches (e.g., PROTAC degraders) to manipulate cellular and organismal function and fate using small molecules (“drug-like” compounds) to artificially recruit ubiquitin ligases to degrade proteins of interest. Small molecule-mediated TPD enables the transient removal of a protein to alter specific processes or events but, when the small molecule is removed, normal function is regained. This contrasts with genetic methods, such as CRISPR-Cas9, that are irreversible; TPD allows for targeting of proteins that would be lethal or impact growth and yield if permanently removed. We are exploring TPD to enable faster cereal breeding and increase genetic diversity, expand GM approaches to previously intractable plants and improve success rates of gene editing in plants.

Cereblon is a substrate recognition adaptor for an E3 ubiquitin ligase and a top candidate for recruiting E3 ligases to proteins of interest for degradation via TPD-based approaches. Interestingly, plant Cereblon shows differences in structure and small molecule binding compared to human Cereblon; plant Cereblon function cannot be inferred from Humans but knowing how Cereblon operates is crucial for understanding how TPD can be employed in plants. Cereblon is proposed to be a “rubbish disposal” regulator, removing damaged proteins to prevent toxic stress. However, recent work demonstrates that Cereblon also regulates non-damaged proteins within the cell through an innate “chemical clock” that dictates protein turnover rates. Our pilot work identified many proteins likely regulated by Cereblon involved in environmental stress tolerance, in particular heat stress, and we demonstrated that Cereblon mutants are defective in these pathways. This is particularly relevant as the “chemical clock” theory hypothesises that degradation rates increase with temperature as chemical reaction rates increase, suggesting that Cereblon-mediated protein turnover dictates how plant proteomes are remodelled by, and adapt to, temperature stress to determine physiological and developmental outcomes.

This project aims to understand how Cereblon dictates plant responses to environmental change and how using Cereblon for TPD approaches may impact pant physiology, although ultimately the project specifics will be co-designed with the successful applicant.

The research team will provide training in plant (temperature) physiology and development, molecular biology, chemical biology, targeted protein degradation and protein biochemistry, with a particular technical focus on proteome enrichment approaches, proteomics and western blotting to understand protein substrate selection, ubiquitination and degradation.

Our research community thrives on the diversity of students and staff which helps to   make the University of Dundee a UK university of choice for postgraduate research. We  welcome applications from all talented individuals and are committed to widening      access to those who have the ability and potential to benefit from higher education. 
 

How to apply

Applications are open to Home & International students

See University Fee Status here

Click ‘Apply Now’ to view the application guidance and download the application form