Introduction

Research Groups

Select Research Group Head Prof. Sir Tom Blundell Prof. Kevin Brindle Dr Bill Broadhurst Dr Guy Brown Dr Mark Carrington Prof. Paul Dupree Prof. Gerard Evan - Head of Dept Prof. Richard Farndale Dr Giorgio Favrin Dr Jenny Gallop Dr Nick Gay Dr Andrew Grace Dr Jules Griffin Dr Brian Hendrich Dr Andrew Hesketh Dr Robin Hesketh Dr Matt Higgins Dr Florian Hollfelder Dr Hee-Jeon Hong Prof. Chris Howe Dr Marko Hyvonen Prof. Steve Jackson Dr Tony Jackson Prof. Richard Jackson Prof. Ernest Laue Prof. Peter Leadlay Dr Kathryn Lilley Dr Karen Lipkow Dr Rick Livesey Prof. Ben Luisi Dr Sarah Lummis Dr Juan Mata Dr John McCafferty Prof. Jim Metcalfe Dr Masanori Mishima Dr Eric Miska Dr Tom Monie Dr Helen Mott Dr Natasha Murzina Dr Daniel Nietlispach Dr Darerca Owen Prof. Steve Oliver Dr Luca Pellegrini Dr Markus Ralser Dr Nick Robinson Prof. George Salmond Dr Deirdre Scadden Dr José Silva Prof. Austin Smith Prof. Chris Smith Dr Nancy Standart Prof. Dame Jean Thomas Dr Aviva Tolkovsky Dr Martin Welch Dr Joyce Wong Dr Nianshu Zhang

Service & Research Support Facilities

Select by Subject or Manager DNA Sequencing Facility . . . . . Mr John Lester _______________________________ Quantitative Proteomics . . . . . Dr Kathryn Lilley _______________________________ Proteomics Core Services . . . . . Dr Mike Deery _______________________________ Protein & Nucleic Acid Chemistry . . . . . Dr Len Packman _______________________________ Metabolomics . . . . . Dr Jules Griffin _______________________________ Baculovirus Facility . . . . . Dr Darerca Owen _______________________________ Biophysics Facility . . . . . Dr Katherine Stott _______________________________ Crystallographic X-ray Facility . . . . . Dr Dima Chirgadze _______________________________ NMR spectroscopy . . . . . Dr Daniel Nietlispach _______________________________ Fermentation Facility . . . . . Dr Nianshu Zhang _______________________________ Bioinformatics & Computational Biology Services . . . . . Dr Jenny Barna _______________________________ Computer & IT Support . . . . . Dr Erik Timmers _______________________________

Past members last known active weblink

Select past member of Department Dr Stephen Bell Prof. Jonathan Blackburn Dr David Brown Dr Pak-Lee Chau Dr Hal Dixon (deceased) Dr Jessica Downs Prof. David Ellar Dr Paul Kemp Dr Simon Lovell Dr Kenji Mizuguchi Dr Massimo Paoli Prof. Richard Perham Dr Peter Reynolds Dr Philip Rubery Dr Gerry Smith Dr Margaret Sunde Prof. Jamie Vandenberg Dr Kira Weissman

Reset Menus

Mechanisms of Translation Initiation Site Selection on Eukaryotic Cellular and Viral mRNA

Research Groupings: Structural and molecular cell biology | Functional genomics, systems biology and genetic medicine

We are interested in the mechanism of initiation site selection on eukaryotic mRNAs, and the ways in which viruses have subverted this mechanism. Of all the steps in protein synthesis, initiation is the one which differs most radically between eukaryotes and prokaryotes, requiring no less than 11 separate initiation factor proteins (a total of 26 polypeptides of aggregate mass >1600 kDa) in eukaryotes as against 3 such factors, each a single polypeptide chain, in eubacteria.

The initiation site in almost all eukaryotic cellular mRNAs is the 5’-proximal AUG triplet. This is accessed by a process in which the small ribosomal subunit scans the mRNA from the capped end, stopping usually at the first AUG (subject to some influence of local sequence context). If the first AUG is followed by a short open-reading frame (<~20 codons), some ribosomes may resume scanning and re-initiate translation at a downstream AUG. Our current and recent interests include the ‘mechanics’ of the scanning process, and the reason why reinitiation usually occurs only if the first cistron is short.

The major mechanisms of initiation site selection on eukaryotic mRNA: (a) initiation site selection by scanning (and subsequent reinitiation by some ribosomes if the first cistron is short); (b) IRES-dependent initiation (in the context of the dicistronic mRNA assay for IRESs). The small ribosomal subunit (with associated initiation factors and Met-tRNA) is shown in red, the large subunit in blue, and the black filled circle denotes the 5’-cap.

In some cases, initiation is by direct ribosome entry at an internal site in the mRNA, dependent on a substantial (up to 450 nt.) cis-acting motif in the RNA, known as an IRES (for ‘internal ribosome entry segment’), which is generally highly structured. IRESs are identified by the fact that when inserted as the intercistronic spacer of a dicistronic mRNA they promote translation of the downstream cistron (see figure). Three entirely distinct types of IRES have been identified amongst different RNA virus genera: (i) animal picornaviruses; (ii) hepatitis C virus and pestiviruses; and (iii) the dicistrovirus family of insect viruses. The questions concerning internal initiation on each type of IRES that we have addressed and are continuing to examine, include: (a) where is the actual ribosome entry site; (b) which canonical initiation factors and what additional cellular proteins are needed for initiation; and (c) how fundamentally different are the scanning and IRES-dependent mechanisms of initiation?

Lab members
Rachel Allison, Panagiota Kafasla, Tuija Poyry

References