We are a research team at the University of Cambridge, based on the Cambridge Biomedical Campus. We seek to develop and exploit genetic technologies to identify novel therapeutic targets.
Biography
Richard recently started his independent laboratory at the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID). The goal of his work is to develop and exploit genetic tools to understand how the ubiquitin-proteasome system achieves selective protein degradation. Richard’s interest in genetics began as a PhD student with Prof. Paul Lehner at the Cambridge Institute of Medical Research, where he developed genetic screens in haploid human cells to study viral E3 ubiquitin ligases. Then, as a Sir Henry Wellcome Postdoctoral Fellow working in the lab of Prof. Steve Elledge at Harvard Medical School, he discovered a range of novel degradative pathways through which Cullin-RING E3 ligases target degrons located at the extreme N- and C-termini of their substrates. The expression screening techniques that he developed to interrogate E3 ligase-substrate interactions form the basis of work in his new lab.
Research
I am interested in using novel genetic technologies coupled with the power of next-generation sequencing to identify functions for novel genes involved in cellular processes.
Working in the laboratory of Professor Paul Lehner, I have spent my doctoral research performing non-lethal forward genetic screens in the near-haploid KBM7 cell line. Such screens are a powerful technique to examine gene function in human cells, and are readily adaptable to the study of essentially any cellular process. This work has assigned functions to two poorly characterised genes, PLP2 and TMEM129, which are hijacked by viral proteins that interfere with antigen presentation by MHC-I molecules. More recently we have used this approach to identify a novel component of the epigenetic silencing machinery – the HUSH complex - which is responsible for heterochromatin maintenance in human cells, and which could be important in the context of viral latency.
The rapid recent development of CRISPR/Cas9 technology offers an alternative method to carry out forward genetic screens in human cells. The focus of my current work is to utilise the power of haploid and CRISPR screens to identify further novel genes involved in chromatin regulation.
Publications
Dipeptidyl peptidases and E3 ligases of N-degron pathways cooperate to regulate protein stability. J Cell Biol PubMed 05 Aug 2024
Mechanism of Ψ-Pro/C-degron recognition by the CRL2FEM1B ubiquitin ligase. Nat Commun PubMed 26 Apr 2024
Author Correction: Defining E3 ligase-substrate relationships through multiplex CRISPR screening. Nat Cell Biol PubMed 01 Feb 2024
Defining E3 ligase-substrate relationships through multiplex CRISPR screening. Nat Cell Biol PubMed 01 Oct 2023
High-throughput, targeted MHC class I immunopeptidomics using a functional genetics screening platform. Nat Biotechnol PubMed 01 Jul 2023
Timms RT*, Tchasovnikarova IA*, Matheson NJ, Wals K, Antrobus R, Göttgens B, Dougan G, Dawson MA, Lehner PJ (2015) Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. Science 348: 1481-1485
van den Boomen D, Timms RT, Grice GL, Stagg HR, Skjødt K, Dougan G, Nathan JA, Lehner PJ (2014) TMEM129 is a Derlin-1 associated ERAD E3 ligase essential for virus-induced degradation of MHC-I. Proc. Natl. Acad. Sci. USA 111: 11425-11430
Timms RT, Duncan LM, Tchasovnikarova IA, Antrobus R, Dougan G, Weekes MP, Lehner PJ (2013) Haploid genetic screens identify an essential role for PLP2 in the downregulation of novel plasma membrane targets by viral E3 ubiquitin ligases. PLoS Pathogens 9(11): e1003772
Timms RT*, Duncan LM*, Zavodszky E, Cano F, Dougan G, Randow F, Lehner PJ (2012) Fluorescence-based phenotypic selection allows forward genetic screens in haploid human cells. PLoS ONE 7(6): e39651
*equal contribution
