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Genetic dissection of the ubiquitin-proteasome system


Department of Medicine

Cambridge United Kingdom Bioinformatics Biotechnology Cancer Biology Cell Biology Genetic Engineering Genetics Genomics Immunology Molecular Biology Molecular Genetics

About the Project

How can we target E3 ubiquitin ligases for therapeutic benefit? Work in the Timms laboratory centres around exploiting cutting-edge genetic technologies to study the ubiquitin-proteasome system (UPS). The UPS is the major route through which the cell achieves selective protein degradation, and hence the system plays a critical role in essentially all cellular processes. UPS components are a largely untapped source of potential drug targets, but an enhanced understanding of how E3 ubiquitin ligases select their substrates is required to guide the development of novel therapeutics.

The successful candidate will undertake a three-year research project using a combination of expression screening techniques and loss-of-function CRISPR screening approaches with the goal of (1) identifying substrates of E3 ubiquitin ligases, (2) delineating the specific molecular features ("degrons") that dictate substrate recognition, and (3) exploring how these processes are corrupted in the context of viral infection and autoimmune disease. This studentship is ideal for someone passionate about genetics who is eager to exploit the latest technologies in areas such as CRISPR/Cas9-mediated genome editing, microarray oligonucleotide synthesis, pooled lentiviral library screens, and next-generation sequencing and associated computational approaches. At the end of the studentship you will have gained a broad range of key experimental and transferable skills, which will provide an effective springboard towards a successful research career in the biological sciences.

You will work in the Timms laboratory, based in the Cambridge Institute for Therapeutic Immunology and Infections Disease (CITIID) which is situated at the heart of the Cambridge Biomedical Campus. The Institute is housed within the brand new Jeffrey Cheah Biomedical Centre building, thus benefiting from modern facilities and state-of-the-art equipment. You will also become a member of one of the 31 Cambridge Colleges, through which you will have access to accommodation and a wide variety of student clubs, societies and activities.

Further details are available here.

About the Timms Lab

The goal of research in the Timms lab is to apply the latest genetic technologies to uncover novel functions for human genes, with our primary focus being the regulation of cellular processes by the ubiquitin-proteasome system. We exploit a range of high-throughput genetic screening techniques to uncover novel pathways regulated by ubiquitin, which we study both in healthy human cells and in the context of viral infection and autoimmune disease. We measure the stability of GFP-tagged proteins by performing expression screens in human cells, either using a human ORFeome library comprising ~14,000 barcoded human ORFs or custom libraries generated through microarray-based oligonucleotide synthesis, and identify the cellular machinery involved by combining these expression screens with loss-of-function CRISPR/Cas9 screens. Detailed follow-up of individual pathways of interest is achieved through a variety of standard genetic and biochemical approaches.

For more information, visit the lab website.


Funding Notes

For home students, the position is fully funded: you will receive an annual stipend of £18,000, and your University tuition fees will be fully covered for three years starting from October 2021. Regretfully, no additional funding is available to support students not qualifying for home fee status.

References

Timms RT and Koren I (2020) Tying up loose ends: the N-degron and C-degron pathways of protein degradation. Biochem Soc Trans, 48 (4): 1557-1567
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Timms et al. (2019) A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation. Science, 365 (6448): eaaw4912
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Koren I, Timms RT et al. (2018) The Eukaryotic Proteome Is Shaped by E3 Ubiquitin Ligases Targeting C-Terminal Degrons. Cell, 173 (7): 1622-1635

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