The goal of our work is to develop and exploit novel genetic technologies to illuminate new functions of human genes. Our primary focus is the ubiquitin-proteasome system (UPS), the major route through which the cell achieves selective protein degradation. The importance of the UPS in infection and immunity is underscored by the range of mutations in ubiquitin system components that cause immune disease, and the elaborate strategies employed by pathogens to hijack the ubiquitin system to promote their survival.
How specificity is achieved within the ubiquitin system remains an important unanswered question. The E3 ubiquitin ligases, of which there are ~800 encoded in the human genome, are thought to selectively recognise specific ‘degron’ motifs found in substrate proteins. However, our knowledge of degron motifs remains remarkably sparse, preventing us from being able to predict the relevant substrates of E3s. Attaining such a systems-level understanding of the ubiquitin system will be critical if we are to appreciate how it can best be manipulated for therapeutic benefit.
We exploit a range of high-throughput genetic screening techniques to uncover novel pathways regulated by the ubiquitin system. Using a combination of microarray-based oligonucleotide synthesis, lentiviral expression screens, CRISPR/Cas9-mediated mutagenesis and next-generation sequencing, we aim to (1) identify substrates of E3 ubiquitin ligases, (2) characterise the molecular features that enable selective substrate recognition, and (3) explore how these processes are corrupted in the context of viral infection and autoimmune disease.
Timms RT and Koren I. Tying Up Loose Ends: The N-degron and C-degron Pathways of Protein Degradation. Biochemical Society Transactions 2020. DOI: 10.1042/BST20191094.
Timms RT … Elledge SJ. A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation. Science 2019. DOI: 10.1126/science.aaw4912
Koren I, Timms RT … Elledge SJ. The Eukaryotic Proteome Is Shaped by E3 Ubiquitin Ligases Targeting C-Terminal Degrons. Cell 2018. DOI: 10.1016/j.cell.2018.04.028
Tchasovnikarova IA*, Timms RT * … Lehner PJ. Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2. Nature Genetics 2017. DOI: 10.1038/ng.3878
Timms RT … Lehner PJ. Genetic dissection of mammalian ERAD through comparative haploid and CRISPR forward genetic screens. Nature Communications 2016. DOI: 10.1038/ncomms11786
Tchasovnikarova IA*, Timms RT * … Lehner PJ. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. Science 2015. DOI: 10.1126/science.aaa7227
Timms RT … Lehner PJ. Haploid genetic screens identify an essential role for PLP2 in the downregulation of novel plasma membrane targets by viral E3 ubiquitin ligases. PLoS Pathogens 2013. DOI: 10.1371/journal.ppat.1003772