Regulation of genome stability by the ATM and ATR protein kinases

Lead Research Organisation: MRC Protein Phosphorylation Unit

Abstract

DNA, the genetic material in our cells, is frequently damaged. Since the instructions for the proper running of the cell are contained within DNA, damage to this material poses the risk of permanent changes to these instructions, called mutations, that can have an adverse effect on cell behaviour. Mutations are the cause of cancer and other debilitating diseases. Normally, cells quickly realise when DNA has been damaged and they fix it. However, when the level of DNA damage is high or when repair is sub-optimal, the cell can't cope and launches what is known as the DNA damage response. This shuts off normal cell function to give the cell plenty of opportunity to find the damage and greatly increases the capacity to repair it. We are working on two important proteins, ATM and ATR that find DNA damage and initiate the DNA damage response. We are trying to understand how they find the damaged DNA, how they trigger the DNA damage response and what other proteins are involved. In this way, we hope to understand in detail the normal cellular processes that go wrong in cancer and how we might correct them in diseased cells, or prevent them from going wrong in the first place.

Technical Summary

Defects in DNA repair or in the ability of cells to slow cell cycle progression after DNA damage can increase cellular mutation rates and cause genome instability leading to variety of debilitating diseases that are accompanied by heightened predispostion to cancer. DNA lesions trigger a highly conserved signal transduction pathway that regulates many aspects of the cellular response to DNA damage and the principal regulators of this pathway are the ATM and ATR protein kinases, critical regulators of genome stability. These kinases rapidly translocate to sites of DNA damage or to stalled DNA replisomes where they are activated by mechanisms that are not yet clear. This causes phosphorylation of a range of proteins including the BRCA1 and p53 tumour suppressors, and the conserved Chk1 and Chk2 protein kinases that when activated by ATM/ATR in turn phosphorylate effectors of cell cycle progression. It is still not known how they carry out many of their cellular functions at the molecular level. For example, it is not clear how ATM and ATR increase cellular DNA repair capacity, how ATR prevents firing of origins of replication when the DNA replication machinery stalls, how these kinases restore chromatin configuration after DNA damage or how they promote recovery from DNA damage. The main goal of my laboratory is to understand how ATM/ATR regulate these processes. We are using several approaches biochemical, genetic and structural - to investigate how ATM/ATR recognise their substrates, what these substrates are, and how these targets contribute to the maintenance of genome stability. We are also using yeast to investigate how, at the molecular level, stalled replisomes bypass replication fork-blocking lesions.We identified several new targets of ATM and ATR and have investigated their cellular functions using budding yeast as a model organism. Phosphorylation of Esc4 by ATR, for example, is essential for the resumption of DNA replication when the DNA replication apparatus stalls at sites of DNA damage. Another new target of ATM and ATR, Slx4, prevents abnormal DNA structures from arising in the vicinity of stalled replication forks. Recently we found that Slx4 is an important regulator of the ability of stalled replisomes to bypass replisome-blocking lesions and we are currently investigating the molecular mechanisms involved. We are currently studying human Slx4-containing complexes and their role(s) in maintenance of genome stability. In mammalian cells we have shown that phosphorylation of the 53BP1 tumour suppressor at Ser25 by ATM caused 53BP1 to physically associate with the hPTIP mediator protein that we identified previously. Interaction of these two proteins is essential for intact responses to DNA damage and we are currently investigating this at the molecular level.

Publications


10 25 50
Davis EJ (2012) DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA damage. in Nature structural & molecular biology
Gardiner M (2008) Identification and characterization of FUS/TLS as a new target of ATM. in The Biochemical journal
 
Description AICR Project Grant
Amount £150,000 (GBP)
Organisation Association for International Cancer Research (AICR) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2006 
End 04/2009
 
Description AICR Project Grant
Amount £167,000 (GBP)
Organisation Association for International Cancer Research (AICR) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 06/2010 
End 06/2013
 
Description Chromatin and the DNA damage response
Amount £250,000 (GBP)
Organisation Marie Curie Actions 
Department Initial Training Networks (ITN)
Sector Charity/Non Profit
Country Global
Start 09/2013 
End 09/2016
 
Description FP7 Marie Curie Initiative
Amount € 250,000 (EUR)
Organisation European Commission (EC) 
Sector Public
Country European Union (EU)
Start 10/2012 
End 10/2016
 
Description Project Grant
Amount £240,000 (GBP)
Organisation British Society for Haematology (BSH) 
Sector Learned Society
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 03/2010 
End 03/2013
 
Description Wellcome/MRC Neurodegenerative Disease Initiative
Amount £250,000 (GBP)
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2010 
End 10/2013
 
Title Antibodies 
Description Antibodies against a wide variety of human and moue DNA repair proteins including XPF, ERCC1, MUS81, EME1, SLX4, FAN1 
Type Of Material Biological samples 
Year Produced 2013 
Provided To Others? Yes  
Impact Papers 
 
Title Cells from SLX4 knockout mouse embryos 
Description Mice lacking 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2012 
Provided To Others? Yes  
Impact Cells from SLX4 knockout mouse embryos 
 
Title GFP-DVC1 cells 
Description Cells stably expressing GFP-DVC1 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact Identification of DVC1 as a novel regulator of DNA repair 
 
Title GFP-FAN1 
Description Cell liens stably expressing GFP-FAN1 
Type Of Material Cell line 
Year Produced 2010 
Provided To Others? Yes  
Impact NA 
 
Title GFP-SLX4 
Description Cells expressing GFP-SLX4 
Type Of Material Cell line 
Provided To Others? No  
Impact PMID: 19595721 
URL http://europepmc.org/abstract/MED/19595721
 
Title SLX1 knockout mice 
Description Mice lacking the SLX1 Holliday junction resolvase 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2011 
Provided To Others? Yes  
Impact Publications 
 
Title SLX1 knockout mice 
Description SLX1 knockout mice 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2012 
Provided To Others? Yes  
Impact We demonstrated that the Slx1 nuclease is an important new regulator of DNA repair 
 
Title SLX4 knockout mice 
Description Mice lacking SLX4 DNA repair protein 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2012 
Provided To Others? Yes  
Impact Several publications; new model of DNA repair 
 
Title Stable cell lines 
Description HEK293 and U2OS cells stably express GFP-tagged forms of a range of DNA repair proteins including DVC1, SLX4, FAN1, MUS81, XPF 
Type Of Material Cell line 
Year Produced 2013 
Provided To Others? Yes  
Impact Papers 
 
Description Analysis of FAN1 function in worms 
Organisation The Wellcome Trust Ltd
Department Wellcome Trust Centre for Gene Regulation and Expression
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We discovered a new DNA repair protein, this group helped with assays we had no experience with.
Collaborator Contribution Publication
Impact Publication
Start Year 2010
 
Description Analysis of homologous recombination in FAN1-deficient cells. 
Organisation Cancer Research UK (CRUK)
Department London Research Institute (LRI)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution It worked the other way round!! And how come I don't get to name the person I collaborated with, just the organisation? This is highly unsatisfactory. I contacted the investigator for help with homologous recombination assays. The resulting data were included in a paper from my lab.
Collaborator Contribution Publication
Impact One publication.
Start Year 2010
 
Description Analysis of the roles of new regulators of genome stability in homologous recombination 
Organisation Medical Research Council (MRC)
Department CRUK/MRC Oxford Institute for Radiation Oncology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution It worked the other way round!! And how come I don't get to name the person I collaborated with, just the organisation? This is highly unsatisfactory. I contacted this scientist for help with homologous recombination assays. The resulting data were included in a several papers from my lab.
Collaborator Contribution Publications
Impact Publications.
Start Year 2008
 
Description Chromatin and DNA repair 
Organisation University of Copenhagen
Country Denmark, Kingdom of 
Sector Academic/University 
PI Contribution Cell biology of MMS22L and TONSL
Collaborator Contribution Analysis of histone modifications modulated by MMS22L and TONSL
Impact Not yet
Start Year 2011
 
Description Control of telomeres by the SLX4 complex 
Organisation Spanish Ministry of Economy and Competitiveness
Department Spanish National Cancer Research Centre (CNIO)
Country Spain, Kingdom of 
Sector Academic/University 
PI Contribution We conceived and designed the project
Collaborator Contribution Help with telomere analysis
Impact Paper in Cell Reports
Start Year 2012
 
Description DNA repair in yeast 
Organisation Brandeis University
Country United States of America 
Sector Academic/University 
PI Contribution We did most of the experiments
Collaborator Contribution Technical expertise, experiments
Impact PMID: 17636031
 
Description DSTT 
Organisation AstraZeneca
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php
Collaborator Contribution Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
 
Description DSTT 
Organisation C.H. Boehringer Sohn AG & Ko. KG
Department Boehringer Ingelheim
Country Germany, Federal Republic of 
Sector Private 
PI Contribution All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php
Collaborator Contribution Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
 
Description DSTT 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php
Collaborator Contribution Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
 
Description DSTT 
Organisation Johnson & Johnson
Department Janssen Pharmaceutica
Country Global 
Sector Private 
PI Contribution All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php
Collaborator Contribution Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
 
Description DSTT 
Organisation Merck (KGaA)
Department Merck Serono
Country Germany, Federal Republic of 
Sector Private 
PI Contribution All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php
Collaborator Contribution Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
 
Description DSTT 
Organisation Pfizer Inc
Country United States of America 
Sector Private 
PI Contribution All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php
Collaborator Contribution Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
 
Description DSTT renewal 2016 
Organisation C.H. Boehringer Sohn AG & Ko. KG
Department Boehringer Ingelheim
Country Germany, Federal Republic of 
Sector Private 
PI Contribution Boehringer-Ingelheim, GlaxoSmithKline and Merck-Serono - each company pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease.
Collaborator Contribution The MRC-PPU benefits in many ways as a result of the DSTT research collaboration.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
Start Year 2016
 
Description DSTT renewal 2016 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Boehringer-Ingelheim, GlaxoSmithKline and Merck-Serono - each company pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease.
Collaborator Contribution The MRC-PPU benefits in many ways as a result of the DSTT research collaboration.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
Start Year 2016
 
Description DSTT renewal 2016 
Organisation Merck (KGaA)
Department Merck Serono
Country Germany, Federal Republic of 
Sector Private 
PI Contribution Boehringer-Ingelheim, GlaxoSmithKline and Merck-Serono - each company pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease.
Collaborator Contribution The MRC-PPU benefits in many ways as a result of the DSTT research collaboration.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
Start Year 2016
 
Description Functional analysis of the deubiquitylase USP45 
Organisation University of Dundee
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We helped with assays and analysis of DNA repair
Collaborator Contribution They conceived the project
Impact Paper under review at EMBO J
Start Year 2013
 
Description MRC Harwell 
Organisation Medical Research Council (MRC)
Department MRC Harwell
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Engage in discussion about mouse lines
Collaborator Contribution Supply of mouse lines to investigate PD mutations and the Rab pathway
Impact On going
Start Year 2015
 
Description Role of SLX4 in DNA repair 
Organisation Erasmus University Rotterdam (Erasmus Universitair Medisch Centrum EUR)
Department University Medical Center
Country Netherlands, Kingdom of the 
Sector Hospitals 
PI Contribution We carried out most experiments, but had help with DNA repair assays from this group
Collaborator Contribution Technical expertise, experiments
Impact PMID: 19595721
Start Year 2009
 
Description Structural analysis of DNA repair nucleases 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution We initiated the project
Collaborator Contribution Structural analysis
Impact A paper in Cell Reports
Start Year 2010
 
Title Small molecule inhibitors for use in combination with platinum-based chemotherapies 
Description We discovered FAN1, a new DNA repair enzyme required to repair DNA damage induced by certain chemotherapy agents. Our data revealed that depleting FAN1 from cells results in hypersensitivity to platinum compounds commonly used in the chemotherapy clinic. We also found that FAN1 overexpression may cause resistance to cisplatin, a common problem in the clinic. So our data make FAN1 an excellent drug target. 
IP Reference WO2012004559 
Protection Patent application published
Year Protection Granted 2012
Licensed No
Impact See above.
 
Title Screening for inhibitors of the FAN1 DNA repair nuclease 
Description Early stage small molecule inhibitors of the FAN1 DNA repair nuclease; done in collaboration with Dundee Drug Discovery Unit 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact WIll investigate use as single agent anti-cancer compound; might sensitize cancers to platinum-based chemotherapeutics by inhibiting repair of platinum-induced DNA damage 
 
Description MRC Cancer Morning 
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 Local
Primary Audience Public/other audiences
Results and Impact Members of the public, patient groups, schoolchildren and local charities attended the MRC Cancer Morning I organised. A lay presentation was follwed by QA session and a tour of facilities

Increased public understanding of science
Year(s) Of Engagement Activity 2013
 
Description Promotional Film made in lab to promote cancer research 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Policymakers/parliamentarians
Results and Impact My lab was the focus of a promotional film shot over two days. The idea was to show how research works, from idea to experiments and back, for the benefit of potential donors to Association of International Cancer research based in St. Andrews.

Help AICR fundraising activities
Year(s) Of Engagement Activity 2013
 
Description Radio interview on the award of £250000 for neurodegenerative disease research 
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 Media (as a channel to the public)
Results and Impact I was interviewed about our work on neurodegenerative disease.

Our work reached a wide audience.
Year(s) Of Engagement Activity 2009
 
Description School visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact Talk to schoolchildren about this research

Sparked interest; aroused curiousity; taught about role of scientist and value to society
Year(s) Of Engagement Activity 2006,2007,2008
 
Description Several radio interviews on nationwide stations about our discovery of FAN1 
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 Media (as a channel to the public)
Results and Impact I was interviewed on several radio stations: SKY, 5 Live, for example on our discovery of FAN1, which I described as a DNA molecular scissors

Our work reached a wide audience
Year(s) Of Engagement Activity 2010
 
Description TV Interview 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I was interviewed on Scottish TV about our discovery of the FAN1 DNA repair protein.

Our work reached a wide audience
Year(s) Of Engagement Activity 2010