Investigating mRNA methyl cap regulation, function and therapeutic potential
Lead Research Organisation:
University of Dundee
Department Name: School of Life Sciences
Abstract
Victoria Cowling's lab at the University of Dundee investigate how proteins are made in human cells, with the aim of uncovering new approaches to stop the growth of cancer cells and parasites. The human body is made up of trillions of cells with many different functions, e.g. skin, muscle, gut cells. Our health is dependent on these cells responding rapidly to the "instructions" they receive from the body on how to function and whether to grow and multiply, rest or die. In this way, trillions of cells can co-ordinate their activities to form the human body. In cancer, our cells become less responsive to these instructions, and grow and divide in an uncontrolled manner. As a result masses of cells accumulate, often forming cancerous tumours. Cancer researchers investigate why cancer cells become unresponsive to instructions from the body, with the aim of developing new therapies to stop cancer cells growing. Cells are built from proteins and therefore for cells to grow and divide, new proteins need to be made. DNA found in our genes holds the "recipe" for making proteins, but it uses a messenger called RNA to provide precise instructions for proteins. Victoria Cowling's lab is investigating how the RNA messenger is made and handled in the cell, and how it is read to make proteins. Specifically, the Cowling group investigates a structure called the "methyl cap" which flags certain RNAs to be used to make proteins. They discovered that the methyl cap can be influenced by cancer-causing oncogenes and that it is needed for a certain oncogenes to function. Encouraged by these initial results, the Cowling group has initiated a programme of research investigating how the methyl cap is synthesized and regulated in the cell, and how this process goes wrong in cancer cells. They are also collaborating with the Dundee Drug discovery unit to use cutting-edge technology to look for new chemical compounds that stop the methyl cap from forming. Such compounds may form the starting point for developing new anti-cancer therapies. Since human parasites are also dependent on the methyl cap to make protein, Dr Cowling is collaborating with Prof Mike Ferguson at the University of Dundee, to investigate targeting the methyl cap in the parasite, T. brucei, which causes African Sleeping Sickness, a debilitating disease for which treatment remains limited.
Technical Summary
We investigate the regulation and function of the mRNA methyl cap with the ultimate aim of developing new families of compounds to inhibit the growth and proliferation of tumour cells and parasites. The methyl cap is a structure added to mRNA during synthesis, marking transcripts for processing and translation initiation. We have made major contributions to the current understanding of the methyl cap. We discovered the first example of methyl cap regulation; c-Myc oncogene upregulates mRNA cap methylation and this is necessary for c-Myc-dependent gene expression and cell proliferation. We discovered an essential activator of the mRNA cap methyltransferase enzyme, RAM.
Fundamental questions remain about how the methyl cap is synthesized, regulated and functions. Answering these questions will have significant impact for our understanding of regulated gene expression, and provide new therapeutic opportunities.
Our objectives:
1 To determine the mechanism by which the methyl cap is synthesised in mammalian cells
2 To determine how cellular signaling pathways regulate the methyl cap, including c-Myc oncogene and CDK-cyclins
3 To determine the function of regulated cap methylation
4 To develop small molecule inhibitors of mRNA cap methylation for use as tools compounds and to investigate their therapeutic potential in both cancer and trypanosome parasites
We will use biochemistry and mass spectrometry to characterize methyl cap synthesis, biophysical techniques including X-ray crystallography to investigate cap methyltransferase structure, transcriptome sequencing and bioinformatics to investigate the function of regulated cap methylation, and the latest screening techniques in collaboration with the Dundee Drug Discovery Unit to identify cap methyltransferase inhibitors. During this fellowship we aim to initiate drug discovery programmes to target tumour cells and trypanosome parasites
Fundamental questions remain about how the methyl cap is synthesized, regulated and functions. Answering these questions will have significant impact for our understanding of regulated gene expression, and provide new therapeutic opportunities.
Our objectives:
1 To determine the mechanism by which the methyl cap is synthesised in mammalian cells
2 To determine how cellular signaling pathways regulate the methyl cap, including c-Myc oncogene and CDK-cyclins
3 To determine the function of regulated cap methylation
4 To develop small molecule inhibitors of mRNA cap methylation for use as tools compounds and to investigate their therapeutic potential in both cancer and trypanosome parasites
We will use biochemistry and mass spectrometry to characterize methyl cap synthesis, biophysical techniques including X-ray crystallography to investigate cap methyltransferase structure, transcriptome sequencing and bioinformatics to investigate the function of regulated cap methylation, and the latest screening techniques in collaboration with the Dundee Drug Discovery Unit to identify cap methyltransferase inhibitors. During this fellowship we aim to initiate drug discovery programmes to target tumour cells and trypanosome parasites
Planned Impact
We have made fundamental discoveries in medical research which will have impact on other researchers and the public, by many means.
The Nation's health: It is my intention that in the long term, the nation's health benefits from our medical research. Our basic research is investigating how genes are expressed, which will potentially have impact in all areas of medical research in which changes in gene expression cause pathologies. Our basic research may inform and influence other medical research scientists, both in the academic and pharmaceutical sector in the next few months, years or decades. Our more translational research is aimed at cancer cell and parasite growth and proliferation, and if successful is likely to have a significant impact world-wide.
Life Sciences Research, including plant sciences, developmental biology, immunology and neuroscience is likely to be impacted our research. Our discovery that formation of the mRNA methyl cap is regulated is a fundamentally important advance, demonstrating how changes in gene expression result in changes in cellular physiology including growth and proliferation. This impact on other groups research may be occurring right now or in many years time.
The local Dundee community will benefit from our public engagement activities. I host Dundee school children in my lab for 1 day (6 in the last year), with the aim of introducing them to a career in science, and to encourage them to consider going to higher education and university (which most had not). I also take part in the University Open Doors Day, which again informs the local community on what their taxes are being spent, and allows them to ask questions about current cancer research and treatments. I am organising an MRC-PPU open day for cancer patients in 2013, at which they will hear about the research that we do, and how it may progress to new treatments. Hopefully this may provide them with encouragement to stay the course with treatment and to take part in clinical trials.
The drug discovery research community will benefit from the technology used in our research. The methodology and reagents which we are using in the Dundee Drug Discovery Unit, are at the forefront of technology, and therefore likely to benefit the drug discovery community. For example, some of the compound libraries which we are using are made using novel technology and therefore include "unusual" series of compounds. How these compounds behave in various screens will benefit the wider drug discovery community.
The students and postdocs in my lab and college will benefit from the MRC Senior fellowship on many levels. Since they are involved in the cutting edge research, they will gain a broad training in project development and experimental design, effective collaborations, communication with their piers and the wider scientific community, and in publishing papers. They will also receive training in "Generic Skills" that delivers "non-bench" training in skills such as public speaking and public engagement. One of my former postdocs now manages clinical trials, a job which uses the research and organisational skills which she acquired as a postdoc.
The Nation's health: It is my intention that in the long term, the nation's health benefits from our medical research. Our basic research is investigating how genes are expressed, which will potentially have impact in all areas of medical research in which changes in gene expression cause pathologies. Our basic research may inform and influence other medical research scientists, both in the academic and pharmaceutical sector in the next few months, years or decades. Our more translational research is aimed at cancer cell and parasite growth and proliferation, and if successful is likely to have a significant impact world-wide.
Life Sciences Research, including plant sciences, developmental biology, immunology and neuroscience is likely to be impacted our research. Our discovery that formation of the mRNA methyl cap is regulated is a fundamentally important advance, demonstrating how changes in gene expression result in changes in cellular physiology including growth and proliferation. This impact on other groups research may be occurring right now or in many years time.
The local Dundee community will benefit from our public engagement activities. I host Dundee school children in my lab for 1 day (6 in the last year), with the aim of introducing them to a career in science, and to encourage them to consider going to higher education and university (which most had not). I also take part in the University Open Doors Day, which again informs the local community on what their taxes are being spent, and allows them to ask questions about current cancer research and treatments. I am organising an MRC-PPU open day for cancer patients in 2013, at which they will hear about the research that we do, and how it may progress to new treatments. Hopefully this may provide them with encouragement to stay the course with treatment and to take part in clinical trials.
The drug discovery research community will benefit from the technology used in our research. The methodology and reagents which we are using in the Dundee Drug Discovery Unit, are at the forefront of technology, and therefore likely to benefit the drug discovery community. For example, some of the compound libraries which we are using are made using novel technology and therefore include "unusual" series of compounds. How these compounds behave in various screens will benefit the wider drug discovery community.
The students and postdocs in my lab and college will benefit from the MRC Senior fellowship on many levels. Since they are involved in the cutting edge research, they will gain a broad training in project development and experimental design, effective collaborations, communication with their piers and the wider scientific community, and in publishing papers. They will also receive training in "Generic Skills" that delivers "non-bench" training in skills such as public speaking and public engagement. One of my former postdocs now manages clinical trials, a job which uses the research and organisational skills which she acquired as a postdoc.
People |
ORCID iD |
Victoria Cowling (Principal Investigator / Fellow) |
Publications
Dunn S
(2015)
Myc and mRNA capping.
in Biochimica et biophysica acta
Galloway A
(2019)
mRNA cap regulation in mammalian cell function and fate.
in Biochimica et biophysica acta. Gene regulatory mechanisms
Grasso L
(2016)
mRNA Cap Methylation in Pluripotency and Differentiation.
in Cell reports
Varshney D
(2018)
mRNA Cap Methyltransferase, RNMT-RAM, Promotes RNA Pol II-Dependent Transcription.
in Cell reports
Kasprzyk R
(2020)
Direct High-Throughput Screening Assay for mRNA Cap Guanine-N7 Methyltransferase Activity
in Chemistry - A European Journal
Young DF
(2016)
Human IFIT1 Inhibits mRNA Translation of Rubulaviruses but Not Other Members of the Paramyxoviridae Family.
in Journal of virology
Inesta-Vaquera F
(2018)
DHX15 regulates CMTR1-dependent gene expression and cell proliferation.
in Life science alliance
Aregger M
(2016)
CDK1-Cyclin B1 Activates RNMT, Coordinating mRNA Cap Methylation with G1 Phase Transcription.
in Molecular cell
Varshney D
(2015)
SINE transcription by RNA polymerase III is suppressed by histone methylation but not by DNA methylation.
in Nature communications
Description | Role of N6 methylation |
Organisation | University of Dundee |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Investigating the mammalian homologues of protein N6 methyltransferase complexes discovered in plants |
Collaborator Contribution | Investigating the plant homologues of protein N6 methyltransferase complexes discovered in plants |
Impact | Paper in submission |
Start Year | 2014 |
Description | Role of N6 methylation |
Organisation | University of Nottingham |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Investigating the mammalian homologues of protein N6 methyltransferase complexes discovered in plants |
Collaborator Contribution | Investigating the plant homologues of protein N6 methyltransferase complexes discovered in plants |
Impact | Paper in submission |
Start Year | 2014 |
Description | Role of capping in transcription |
Organisation | University of Münster |
Country | Germany |
Sector | Academic/University |
PI Contribution | Providing in vivo data for the project |
Collaborator Contribution | Providing in vitro data for the project |
Impact | Paper being planned |
Start Year | 2013 |
Description | Interview for Nusovus magazine (sent to lay public fundraisers for Tenovus Scotland)) |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Newsletter sent to Tenovus Scotland fundraisers. This will help them raise more money. Public fundraisers understood how their funds had been spent |
Year(s) Of Engagement Activity | 2014 |
Description | Interview for Research Fortnight magazine |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | National |
Primary Audience | Health professionals |
Results and Impact | Interview published in magazine describing how to go about getting awarded and EMBO Young Investigator Award Communication with researchers how to help gain award |
Year(s) Of Engagement Activity | 2014 |
Description | Interview with Journal of Cell Science, "One to watch" |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | I was interviewed on career matters; describing how I made choices, advice for new researchers, etc. The aim was to reach scientists and members of the general public. |
Year(s) Of Engagement Activity | 2015 |
URL | https://www.youtube.com/watch?v=OzW8hXLGgHg |
Description | Open Doors Day 2014 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | About 500 people attended an open doors day with many science activities Various - more informed public- etc |
Year(s) Of Engagement Activity | 2014 |
Description | The GIANT Cell |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Braeview Academy teachers and students helped us build a giant cell over 1 week. This allowed us to discuss cell biology with the students in an informal discussion setting. |
Year(s) Of Engagement Activity | 2016 |
Description | The Giant Worm Family Event at the Mills Observatory |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | The Giant Worm Family Event at the Mills Observatory: My host department, Centre for Gene Regulation, provided worm viewing, DNA making and videos to tell the public about our research.A new winter season at Mills Observatory will begin with an interactive project demonstrating how the 'C. elegans', a minuscule worm that lives in your compost, helps world-leading research carried out at the University of Dundee. The installation is the next project from Outer Space | Inner Space, an interdisciplinary collaboration using research technology to make scientific research accessible to everyone. It is a science communication venture funded by the Centre for Gene Regulation and Expression (GRE) at the University by a Strategic Grant from the Wellcome Trust and hosted by Leisure & Culture Dundee at Mills Observatory. A special launch event taking place on Sunday, 4th December from 2 - 4pm will allow visitors to see the 'Giant Worm' but also meet with scientists, take part in some Christmas science themed craft activities and see the actual worms. The Giant Worm will be available to view in the Observatory's Planetarium during public opening hours from this Sunday until Friday, 31st March 2017, except when the space is in use for Planetarium Shows or Workshops. |
Year(s) Of Engagement Activity | 2016 |
Description | Understanding Cancer Day 24/06/13 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Our objective with this event was to communicate our research to members of the public. We advertised our event through local cancer patient groups and cancer charities. 40 visitors attended including cancer survivors, current cancer patients, relatives of cancer patients, cancer charity workers and school children. The day started with a general introduction to our unit and cancer research in our unit from Prof John Rouse. Prof Rouse, Dr Victoria Cowling and Dr Ian Ganley then explained their current research questions. This session was directly followed by a lively question and answer session, including discussion of our research and cancer research in general. During a refreshment break there was opportunity for more informal discussions with the Prof Rouse, Dr Cowling and Dr Ganley. At this time, lab tours were also conducted including demonstrating mass spectrometry, live cell imaging and the MRC-PPU research area. Dr Matthias Trost, Dr Thimo Kurz and Dr Yogesh Kaluthu assisted with the tours. A number of postdocs and PhD students were also involved throughout the day. 10 MRC staff took part in the day. 4 invitations were issued: 3 cancer patient groups and 1 cancer charity 40 visitors attended Feedback from the visitors was positive. 100% of guests "completely enjoyed the event. There was equivalent interest in: - learning more about cancer research - meeting and chatting to scientists - finding out how medical research affects health 100% wanted to attend a similar event in the future. |
Year(s) Of Engagement Activity | 2013 |