Marie Curie Int Incoming Fellowship
Research Group Leader
Project:The molecular mechanism of protein synthesis
Department of Pathology
University of Cambridge
Our lab studies the molecular mechanism of protein synthesis, with a specific focus on how different viruses interfere with this critical cellular process.
Certain positive sense RNA viruses , such as poliovirus and foot-and-mouth disease virus, possess large highly structured 5’-untranslated regions in their genomes. These structures, referred to as IRESes (internal ribosomal entry sites), are capable of recruiting 40S ribosomal subunits to internal locations in the viral RNA genome, bypassing the requirement for canonical cap-dependent translation. We examine IRES function to determine which host factors are required to support their activity as well as their mechanism of stimulation. These studies are providing incites into our understanding of basic viral translation and cellular tropism important during infection. We are now expanding this research to study the non-canonical translation of other viruses that have alternatives to IRESes that facilitate efficient bypass of cap-dependent protein synthesis.
Immune regulation of virus translation
Another aspect of research in our lab is understanding the cellular response to infection and how the immune system specifically inhibits translation of viral RNAs. We characterized the mechanism of repression of viral translation by the interferon-induced proteins IFIT1 and IFIT5. Binding of these proteins to specific 5’-RNA ends that are recognized as ‘non-self’ directly inhibited their translation. We are now examining the downstream effects off IFIT/RNA recognition and the role of oligomeric complex assemblies in regulating the cells response to infection.
- Sweeney TR*, Kumar P*, Skabkin M, Skabkina O, Hellen CU, Pestova TV. (2014) Inhibition of translation by IFIT family members is determined by their ability to interact selectively with the 5’-terminal regions of cap0-, cap1- and 5’ppp- mRNAs. Nucleic Acids Res. 42(5)3228-45 (* Joint first author)
- Sweeney TR, Abaeva I, Pestova TV, Hellen, CU. (2014) The mechanism of translation initiation of Type 1 picornavirus IRESs. EMBO J., 33(1):76-92.
- Roqué Rosell N, Mokhlesi L, Milton NE, Sweeney TR, Zunszain PA, Curry S, Leatherbarrow RJ. (2014) Design and synthesis of irreversible inhibitors of Foot-and-mouth disease virus 3C protease. Bioorg. and Med. Chem Letters. 24(2):490-4.
- Dhote V, Sweeney TR, Kim N, Hellen CU, Pestova TV. (2012) Roles of individual domains in the function of DHX29, an essential factor required for translation of structured mammalian mRNAs. PNAS,109(46):E3150-9.
- Sweeney TR, Dhote V, Yu Y, Hellen CU. (2012) A distinct class of internal ribosomal entry site in members of the Kobuvirus and proposed Salivirus and Paraturdivirus genera of the Picornaviridae. J Virol., 86(3):1468-86.
- Yu Y, Sweeney TR, Kafasla P, Jackson RJ, Pestova TV, Hellen CU. (2011) The mechanism of translation initiation on Aichivirus RNA mediated by a novel type of picornavirus IRES. EMBO J., 30(21):4423-36.