How do microRNAs regulate translation?
Lead Research Organisation:
MRC Toxicology Unit
Department Name: UNLISTED
Abstract
Recently, a completely new way of controlling gene expression has been identified. This has emerged as a result of the discovery of a whole new class of genes which, unlike most genes, do not produce proteins. Instead they make very small RNA molecules, called microRNAs. There are at least 700 microRNAs within the human genome, each of which has a different function. They work by binding to the messenger RNA molecules expressed from other genes and inhibiting the production of the proteins made from these genes. Each of these 700 small molecules is believed to interact with hundreds of other genes, thus adding to the complex regulation of the human genome. Already it has become clear that malfunction of microRNA regulation is associated with a growing list of human diseases, including cancer, diabetes, and viral infections. Importantly, the mechanisms by which these small RNA molecules inhibit the expression of other genes are not known. To develop new drugs it is essential for us to understand this process and how any malfunctions influence human disease. The experiments proposed here will allow us to discover what these mechanisms are.
Technical Summary
MicroRNAs are non-coding, 21-25 nucleotide RNA molecules that base pair imperfectly to the 3' UTRs of target mRNAs and repress synthesis of the corresponding proteins. Approximately 700 miRNAs have been identified in humans and it has been estimated that they regulate at least 60% of all protein coding mRNAs. Already it has become clear that malfunction of microRNA regulation is associated with a growing list of human diseases, including cancer, diabetes and viral infection. Moreover, many major pharmaceutical companies are interested in developing microRNAs therapies to modulate gene expression and so treat a variety of diseases. However, for the development of specific pharmacological inhibitors that target these small RNAs it is necessary to characterise the mechanism(s) used by microRNA to regulate gene expression. Recently we have found that two distinct types of microRNA repression exist, with one acting at the initiation of protein synthesis and the other at a post-initiation event (Kong et al., 2008, PNAS). At present it is unclear how these two types of microRNA repression regulate translation and, indeed, many potential mechanisms have been proposed for each type of repression without a clear answer coming to light. The aim of this proposal is to systematically examine each step in the translation process, either to eliminate or define its involvement in the repression mechanism. The goals of this fellowship are broken down into three distinct sections to determine:
1) Which components of the cap-binding complex are regulated by miRNAs?
2) Does initiation play any functional role in the post-initiation repression?
3) Do members of the Argonaute (Ago) family of proteins play a direct role in translational regulation and in translational repression by microRNAs? In particular do these proteins regulate translation at the level of [GTP.eIF2.Met-tRNAi] ternary complex formation and do microRNAs affect this activity?
1) Which components of the cap-binding complex are regulated by miRNAs?
2) Does initiation play any functional role in the post-initiation repression?
3) Do members of the Argonaute (Ago) family of proteins play a direct role in translational regulation and in translational repression by microRNAs? In particular do these proteins regulate translation at the level of [GTP.eIF2.Met-tRNAi] ternary complex formation and do microRNAs affect this activity?
People |
ORCID iD |
Martin Bushell (Principal Investigator) |
Publications
Description | AstraZeneca collaborative gift |
Amount | $200,000 (USD) |
Funding ID | Not known |
Organisation | AstraZeneca |
Department | Research and Development AstraZeneca |
Sector | Private |
Country | United Kingdom |
Start | 08/2016 |
End | 09/2021 |
Description | CRT translational control allience |
Amount | £23,000,000 (GBP) |
Organisation | Cancer Research Technology (CRT) |
Sector | Private |
Country | United Kingdom |
Start | 05/2018 |
End | 06/2021 |
Description | CRUK SMERP |
Amount | £400,000 (GBP) |
Funding ID | C1451/A22598 |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2017 |
End | 02/2019 |
Description | New therapeutic strategy to specifically target the oncogenic function of eukaryotic translation initiation factor 4A1 |
Amount | £296,000 (GBP) |
Funding ID | C20673/A30062 |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2020 |
End | 02/2023 |
Description | Cancer Research Technology mRNA Translation |
Organisation | Cancer Research Technology (CRT) |
Country | United Kingdom |
Sector | Private |
PI Contribution | This is a drug discovery pipeline around translational control. I am a led PI within this consortium directly contributing to multiple projects. |
Collaborator Contribution | CRT are conducting the drug discovery activities within this alliance. |
Impact | I outputs currently that I can comment upon. |
Start Year | 2017 |
Description | Invited Speaker Sussex Univ |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker at Sussex University. Gave a talk on translation control and changed the way people think about this level of gene expression control |
Year(s) Of Engagement Activity | 2019 |
Description | Invited Speaker Wurburg |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker in Wurzburg Germany. I gave a talk to science in the area and got great feedback and changed the way they think about translational control |
Year(s) Of Engagement Activity | 2020 |
Description | Invited speaker Dundee |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker at the University of Dundee. Gave a talk on translational control and changed the way they think about this level of gene expression control. |
Year(s) Of Engagement Activity | 2019 |
Description | Invited speaker Galway |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker Galway Ireland. Gave a talk on translational control and changed the way they think about this level of gene regulation. |
Year(s) Of Engagement Activity | 2019 |
Description | Invited speaker RNAi2014 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | The talks was to a wide range of people including people from industry and my talk sparked a large discussion afterwards. Recognition within the field has increased since. In addition I have been invited back to give another talk next year at RNAi2015. |
Year(s) Of Engagement Activity | 2014 |
Description | Invited speaker european society of toxicologist |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | To talk to the European Society of toxicologist. |
Year(s) Of Engagement Activity | 2021 |
Description | Invited talk Keele |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | keynote/invited speaker |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | My Keynote talk at this mini-Symposium sparked a great debate about the research Greater collaboration between my laboratory and the Keele |
Year(s) Of Engagement Activity | 2014 |
Description | Invited talk Sussex |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | My presentation sparked a debate about the research field. Greater collaboration between research groups at Sussex and us. |
Year(s) Of Engagement Activity | 2014 |
Description | Invited talk in Toulouse France |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | 100 students post-docs and IP attended the lecture and this sparked off much debate on how RNA is involved in DNA repair. |
Year(s) Of Engagement Activity | 2016 |
Description | Keynote speaker at LARP Society Stockton House UK |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I give a keynote address at this important meeting that only occurs every two years between the US and UK. It took place at Stockton House, Nick Jenkins hosted and attended sessions. |
Year(s) Of Engagement Activity | 2016 |
Description | MRC centenary day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | Yes |
Type Of Presentation | Workshop Facilitator |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | The whole laboratory was heavily involved in the open day at the Unit in June 2013 for the MRC centenary day . My laboratory recreated a crime scene and showed people how to load DNA gels and how DNA finger printing work. The whole day was a great achievement and we had around 500 people come to the day. Main members of the public commented how great the day was and asked if we were doing it again. |
Year(s) Of Engagement Activity | 2013 |
Description | Organiser for Beatson International Science Meeting |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | I was one of the organisers for this meeting which brought in people from all over the world to talk about their recent results. One of the sessions was focused on translational control which I run and talked in. |
Year(s) Of Engagement Activity | 2019 |
Description | Royal pathology Society invited speaker |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation was to the Royal Society of pathologist. To update them in emerging technologies round RNA based therapeutic and prognostic approaches. |
Year(s) Of Engagement Activity | 2022 |
Description | School Visit |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Type Of Presentation | Workshop Facilitator |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | 30 Primary School pupils visited the Unit for a day, had a couple of lectures and conducted basic experiments isolating DNA and running gels. The pupils were very excited by their time in the Unit and more wanted to do science after the day as they fund it interesting and fun |
Year(s) Of Engagement Activity | 2010,2011,2012 |
Description | Session Chair and invited speaker Gordon research Conference - Post-transcriptional Gene regulation USA |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | High profile engagement with the many research leaders |
Year(s) Of Engagement Activity | 2016 |
Description | TUK 2014 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | workshop facilitator |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | I was an organiser of Translation UK which bring together the whole of the UK community (and some international researcher). This has greatly increase my recognition within the field. |
Year(s) Of Engagement Activity | 2014 |
Description | Three radio interviews |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Type Of Presentation | Paper Presentation |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I was interviewed by three radio stations was around the world including Radio New Zealand and Canadian Broadcasting Corporation about a recent paper published from the Unit arresting neurodegeneration in mice. This reached a wide number of people around the world covering major countries. |
Year(s) Of Engagement Activity | 2013 |
URL | http://www.radionz.co.nz/audio/player/2572678 |
Description | Translation UK 2020 organiser |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | This is a major meeting for the whole field and occurs yearly. I was an organiser for this meeting. Importantly this year we had a large number of people from industry activity developing drugs to target this field and they sponsored this meeting and chaired a session. Got great feed back about this meeting and how good it was. This was organiser by the biochem doc. |
Year(s) Of Engagement Activity | 2019 |
Description | Undergraduate lecture at Nottingham University on further medicines |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Undergraduate students |
Results and Impact | I was invited to give a lecture to undergrad at Nottingham University on Further medicines. They were very excited about the possibilities of using RNA in medicines |
Year(s) Of Engagement Activity | 2016 |