Chromosome maintenance and repair in health and disease
Lead Research Organisation:
University of Dundee
Department Name: UNLISTED
Abstract
The DNA in our cells is the blueprint, or “instruction manual” required for the proper functioning of cells. A major problem for cells is DNA is very frequently damaged as a result of cross-reactivity with agents that come from outside the cell such as sunlight and chemicals found in food, and also from agents that occur normally inside cells. These agents induce staggering array of DNA lesions every day that if left unrepaired could alter the instructions encoded in DNA resulting in “mutations”. Mutations are responsible for a wide range of human diseases such as cancer. The research in my laboratory is aimed at understanding how cells detect, signal and repair damaged DNA in order to prevent mutations and disease. We also aim to understand how defective DNA repair can cause disease. Ironically turning off DNA repair can be very effective in treating certain types of cancer and we are developing new ways of inhibiting DNA repair with a view to devising new anti-cancer therapies.
Technical Summary
Genomic DNA is frequently subjected to insults that damage DNA, and if not rectified the resulting DNA lesions can cause mutations and human disease. Some forms of DNA damage block DNA replication, and cells have evolved protective mechanisms for preventing genome disintegration in the face of these and other obstructions. My laboratory focuses on the molecular mechanisms underlying the signalling and repair of DNA damage, especially those that perturb DNA replication, with emphasis on control of these mechanisms by phosphorylation and ubiquitylation. We are particularly keen to understand how derailment of DNA repair causes disease. In recent years, we have become interested in how cells repair DNA inter-strand crosslinks (ICLs), lesions that potently block DNA replication. ICL repair is important to study as defective ICL repair gives rise to Fanconi anemia (FA), a recessive disorder characterized by developmental defects, bone marrow failure and cancer predisposition. Furthermore, the anti-proliferative effects of some of the most commonly used anti-cancer drugs rely on induction of ICLs, and therefore understanding how ICLs are repaired may pave the way for sensitizing cancers to these drugs and overcoming resistance. In the current quinquennium, our work has provided new mechanistic insight into repair of ICLs and other DNA lesions. Much of our work has focussed on three DNA repair proteins, all of which are recruited to DNA damage sites by UBZ-type ubiquitin-binding domains to prevent genome instability: the structure-selective nuclease FAN1, the scaffold protein SLX4 which coordinates three separate structure-selective nucleases, and the DVC1/SPRTN protease. We have also uncovered new roles for the E3 ubiquitin ligase RFWD3 mutated in a new FA subtype.
Organisations
- University of Dundee (Lead Research Organisation)
- Mount Sinai Hospital (Canada) (Collaboration)
- Oncode Institute (Collaboration)
- University of Copenhagen (Collaboration)
- HARVARD UNIVERSITY (Collaboration)
- Institute for Basic Science , Korea (Collaboration)
- University of Dundee (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- Massachusetts Institute of Technology (Collaboration)
- University of Vienna (Collaboration)
- Dundee Model Railway Club (Collaboration)
- MERCK (Collaboration)
- UNIVERSITY OF OXFORD (Collaboration)
- University of Sussex (Collaboration)
- Laval University Cancer Research Center (Collaboration)
- German Cancer Research Center (Collaboration)
- Loulou Foundation (Collaboration)
- Pfizer Inc (Collaboration)
- University of Seville (Collaboration)
- Telethon Kids Institute (Collaboration)
- UNIVERSITY OF EDINBURGH (Collaboration)
- University of Toronto (Collaboration)
People |
ORCID iD |
Publications
Khanam T
(2021)
CDKL5 kinase controls transcription-coupled responses to DNA damage.
in The EMBO journal
MacKay CI
(2020)
Expanding the phenotype of the CDKL5 deficiency disorder: Are seizures mandatory?
in American journal of medical genetics. Part A
Muñoz IM
(2018)
Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase.
in The EMBO journal
Saredi G
(2019)
Ways to unwind with HROB, a new player in homologous recombination.
in Genes & development
Shroff M
(2020)
A complex comprising C15ORF41 and Codanin-1: the products of two genes mutated in congenital dyserythropoietic anaemia type I (CDA-I).
in The Biochemical journal
Álvarez-Quilón A
(2020)
Endogenous DNA 3' Blocks Are Vulnerabilities for BRCA1 and BRCA2 Deficiency and Are Reversed by the APE2 Nuclease.
in Molecular cell
Related Projects
| Project Reference | Relationship | Related To | Start | End | Award Value |
|---|---|---|---|---|---|
| MC_UU_00018/1 | 01/04/2018 | 31/03/2024 | £4,394,000 | ||
| MC_UU_00018/2 | Transfer | MC_UU_00018/1 | 01/04/2018 | 31/03/2024 | £2,542,000 |
| MC_UU_00018/3 | Transfer | MC_UU_00018/2 | 01/04/2018 | 31/03/2024 | £3,121,000 |
| MC_UU_00018/4 | Transfer | MC_UU_00018/3 | 01/04/2018 | 31/03/2024 | £2,751,000 |
| MC_UU_00018/5 | Transfer | MC_UU_00018/4 | 01/04/2018 | 31/03/2024 | £3,744,000 |
| MC_UU_00018/6 | Transfer | MC_UU_00018/5 | 01/04/2018 | 31/03/2024 | £2,520,000 |
| MC_UU_00018/7 | Transfer | MC_UU_00018/6 | 01/04/2018 | 31/03/2024 | £2,557,000 |
| MC_UU_00018/8 | Transfer | MC_UU_00018/7 | 01/04/2018 | 31/03/2024 | £2,128,000 |
| Description | Advisor to Loulou Foundation London |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Description | Advisor to a pharmaceutical company setting up gene therapy for CDD |
| Geographic Reach | North America |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | My lab has generated tools that are important in biomarker monitoring gene therapy effort to replace the faulty CDKL5 gene mutated in CDKL5 deficiency disorder (CDD). I am now advising a major pharmaceutical company on how to monitor the effectiveness of their gene therapy efforts. The hope is that the tools we have generated will be useful in clinical trials. |
| Description | Member of Radiation Oncology Special Interest Group |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | I was a member of the MRC Radiation Oncology Advisory Group in 2019, helping to analyse the radiation oncology landscape in the UK, and to define a strategy for funding radiation oncology in the future |
| Description | (ICL CHROM) - DNA interstrand crosslink repair and chromatin remodelling |
| Amount | € 224,933 (EUR) |
| Funding ID | 845448 |
| Organisation | European Commission |
| Sector | Public |
| Country | European Union (EU) |
| Start | 02/2020 |
| End | 01/2022 |
| Description | Characterization of new anti-cancer drug targets involved in DNA repair |
| Amount | £750,000 (GBP) |
| Organisation | Merck |
| Department | Merck Serono |
| Sector | Private |
| Country | Germany |
| Start | 12/2016 |
| End | 12/2020 |
| Description | Characterization of physiological substrates of the NEK1-C21ORF2 complex and the functional impact of ALS-causing mutations |
| Amount | £240,000 (GBP) |
| Organisation | Motor Neurone Disease Association (MND) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 04/2021 |
| End | 10/2023 |
| Description | EMBO Lab start-up grant |
| Amount | £300,340 (GBP) |
| Organisation | Loulou Foundation |
| Sector | Private |
| Country | United Kingdom |
| Start | 01/2016 |
| End | 12/2018 |
| Description | EMBO Long Term Fellowship |
| Amount | £70,000 (GBP) |
| Funding ID | ALTF 951-2018 |
| Organisation | European Molecular Biology Organisation |
| Sector | Charity/Non Profit |
| Country | Germany |
| Start | 02/2019 |
| End | 01/2021 |
| Description | Pfizer Centre for Therapeutics Innovation Collaborative Award |
| Amount | $1,100,000 (USD) |
| Organisation | Pfizer Ltd |
| Sector | Private |
| Country | United Kingdom |
| Start | 03/2021 |
| End | 03/2023 |
| Description | Substrates and regulation of the CDKL5 kinase |
| Amount | £650,000 (GBP) |
| Organisation | Loulou Foundation |
| Sector | Private |
| Country | United Kingdom |
| Start | 01/2016 |
| End | 01/2019 |
| Title | Antibodies against CDKL5 |
| Description | Antibodies that recognize CDKL5 |
| Type Of Material | Antibody |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | These polyclonal antibodies recognises human and mouse orthologues of the CDKL5 kinase mutated in CDKL5 deficiency disorder (CDD). Research into CDKL5, and the development of treatments has been hampered by the lack of antibodies against CDKL5. We developed several polyclonal antibodies that we made available to the CDKL5 community prior to publication. |
| URL | http://emboj.embopress.org/content/early/2018/09/28/embj.201899559 |
| Title | Antibodies against a nuclear target of CDKL5 |
| Description | We carried out a screen to identify specifically the nuclear targets of the CDKL5 kinase mutated in childhood epilepsies and in neurodevelopmental diseases. We raised antibodies against one fo these proteins, which allowed visualization of CDKL5 activity at DNA damage sites in human cells |
| Type Of Material | Antibody |
| Year Produced | 2020 |
| Provided To Others? | No |
| Impact | These are the first phospho-antibodies against a nuclear CDKL5 targets, which allowed visualization of CDKL5 activity at DNA damage sites in human cells |
| Title | Antibodies against phosphorylated CDKL5 |
| Description | Antibodies against the Tyr-171-phosphorylated form of CDKL5 |
| Type Of Material | Antibody |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | These polyclonal antibodies recognises a site of autophosphorylation in the CDKL5 kinase mutated in CDKL5 deficiency disorder (CDD). In principle these could be used as a biomarker of CDKL5 activity status - for example to check if CDKL5 delivered by gene therapy to CDD patients is active. RabMabs will be needed to improve sensitivity. |
| URL | http://emboj.embopress.org/content/early/2018/09/28/embj.201899559 |
| Title | Antibodies against phosphorylated CEP131 S35 |
| Description | Polyclonal antibodies that recognize specifically the form of the the centrosomal protein CEP131 phosphorylated on Ser35 by CDKL5 |
| Type Of Material | Antibody |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | This antibody has revolutionised research into CDKL5 disorder. It allowed us and others for the first time to measure the activity of CDKL5, the kinase mutated in CDKL5 deficiency disorder (CDD), in cells. This in turn allowed us to show that pathogenic mutations in CDKL5 abolish kinase activity. Better antibodies are needed for detection of low level endogenous CEP131 though. |
| URL | http://emboj.embopress.org/content/early/2018/09/28/embj.201899559 |
| Title | Antibodies against phosphorylated MAP1S |
| Description | Antibodies recognizing the form of MAP1S phosphorylated by CDKL5 |
| Type Of Material | Antibody |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | This antibody has revolutionised research into CDKL5 disorder. It allowed us and others for the first time to measure the activity of CDKL5, the kinase mutated in CDKL5 deficiency disorder (CDD), in cells. This in turn allowed us to show that pathogenic mutations in CDKL5 abolish kinase activity. Better antibodies are needed for detection of low level endogenous MAP1S though. |
| URL | http://emboj.embopress.org/content/early/2018/09/28/embj.201899559 |
| Title | Antibodies against the phosphorylated nuclear targets of CDKL5 |
| Description | The nuclear targets of CDKL5 are unknown but recent phospho-proteomic screens in my lab have found the first examples. |
| Type Of Material | Antibody |
| Year Produced | 2020 |
| Provided To Others? | No |
| Impact | These antibodies will be very important in biomarker monitoring in gene therapy efforts to treat CDD, a disease caused by mutations in CDKL5 |
| Title | Automated live-cell imaging of laser micro-irradadiation-induced DNA damage |
| Description | We have set up an automated high-throughput platform for microscopy-based screening for protein recruitment to DNA damage sites |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2022 |
| Provided To Others? | No |
| Impact | A collection of clones for GFP-tagged form of every kinase in human cells A collection of cell lines expressing individually every kinase tagged with GFP |
| Title | C21ORF2 knockout ARPE-19 cell line |
| Description | ARPE-19 cells where the C21ORF2 gene was disrupted using CRISPR technology |
| Type Of Material | Cell line |
| Year Produced | 2021 |
| Provided To Others? | No |
| Impact | First cell line where C21ORF2 was disrupted |
| Title | Collection of U2OS-based cell lines expressing each huamn F-box protein with a GFP tag |
| Description | Collection of U2OS-based cell lines expressing each huamn F-box protein with a GFP tag |
| Type Of Material | Cell line |
| Year Produced | 2020 |
| Provided To Others? | No |
| Impact | Allowed the identification of F-box proteins that are recruited to DNA breaks |
| Title | Collection of clones encoding all human F-box proteins tagged with GFP |
| Description | Collection of cDNA clones encoding all human F-box proteins tagged with GFP, in mammalian expression plasmids |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2020 |
| Provided To Others? | No |
| Impact | The clone collection be useful to those interested in screening F-box proteins for specific functions or patterns of localization |
| Title | Laser microirradiation |
| Description | We purchased, with MRC funds, a powerful state-of-the art confocal microscope equipped with a white-light laser to enable microirradiationto induce DNA damage along a track in the cell nucleus. We have applied this technology to visualise protein accumulation at sites of DNA damage. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | We used this technology to show that pathogenic mutations in the E3 ubiquitin ligase RFWD3 cause Fanconi anaemia because they block the recruitment of RFWD3 to DNA damage sites, by blocking interaction with the substrate RPA. we also used this technology to identify important new regulators of DNA damage responses in human cells, some of which could represent important new anti-cancer drug targets. |
| URL | https://www.ppu.mrc.ac.uk/research/principal-investigator/john-rouse |
| Title | NEK1 knockout ARPE-19 cells |
| Description | ARPE-19 cells made using CRISPR technology |
| Type Of Material | Cell line |
| Year Produced | 2021 |
| Provided To Others? | No |
| Impact | First human cell line disrupted for NEK1 |
| Title | Peptide kinase assay to measure the activity of CDKL5 in vitro |
| Description | We used this technology measure the activity of CDKL5 kinase mutated in CDKL5 deficiency disorder (CDD). We identified three in vivo substrates of CDKL5, and showed that CDKL5 can robustly synthetic peptides based on the amino acid sequence around residue phosphorylated in each substrate. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | This technology allowed us to show that pathogenic CDKL5 mutations associated with CDD are loss-of-function mutations because they abolish kinase activity. Therefore, CDD may be caused by defective phosphorylation of its substrates. |
| URL | http://emboj.embopress.org/content/early/2018/09/28/embj.201899559 |
| Title | Phosphoproteomic approach to identify kinase substrates |
| Description | We developed a state-of-the-art, quantitative phosphoproteomic pipeline for finding substrates of protein kinases which was carefully optimized to increase sensitivity. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | We used this technology to identify the first physiological substrates of the CDKL5 kinase mutated in CDKL5 deficiency disorder. These substrates - MAP1S, CEP131 and DLG5 - represent biomarkers that will be invaluable in disease diagnosis and in the development of gene therapies. They also give clues as to the cellular functions of CDKL5. |
| URL | http://emboj.embopress.org/content/early/2018/09/28/embj.201899559 |
| Title | RAD52 knockout cells |
| Description | Cells in which the RAD52 gene is disrupted |
| Type Of Material | Cell line |
| Year Produced | 2023 |
| Provided To Others? | No |
| Impact | None yet but the cell line will be used to validate RAD52 as a new drug target |
| Title | Mass spectrometry CDKL5 phospho-proteomic dataset |
| Description | The mass spectrometry phospho-proteomics dataset which allowed us to determine substrates of the CDKL5 kinase mutated in CDKL5 disorder was deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD009374. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | Anyone can interrogate these raw data which suggest potential CDKL5 substrates, and validate any of the hits they're interested in. |
| URL | http://emboj.embopress.org/content/early/2018/09/28/embj.201899559 |
| Title | Phospho-proteomic dataset revealing the nuclear targets phosphorylated by CDKL5 |
| Description | Raw MS data comparing the phospho-proteomes of CDKL5 knockout cells expressing wild-type nucleus-restricted CDKL5 or kinase-dead nucleus-restricted CDKL5 |
| Type Of Material | Database/Collection of data |
| Year Produced | 2021 |
| Provided To Others? | Yes |
| Impact | The targets we identified are valuable biomarkers of CDKL5 activity with diagnostic uses as well as the monitoring of the efficacy of gene therapy trials. |
| Title | R-script for analysis of selected reaction monitoring data |
| Description | This algorithm was written to allow analysis of selected reaction monitoring data for the analysis of specific phosphorylation sites in specific proteins |
| Type Of Material | Computer model/algorithm |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | Others can view this algorithm to understand exactly how we analysed SRM datasets, and can use this script, in principle, as a start-point for their own bespoke scripts |
| URL | http://emboj.embopress.org/content/early/2018/09/28/embj.201899559 |
| Description | Analysis of DNA end resection in human cells |
| Organisation | Laval University Cancer Research Center |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | My team discovered a new factor in human cells which controls the choice between the different modes of double strand break repair in human cells |
| Collaborator Contribution | Our collaborators measured DNA end resection rates in human cells lacking our new factor, using state-of-the-art methods they developed |
| Impact | None yet. Paper in the pipeline |
| Start Year | 2020 |
| Description | Analysis of DNA end resection in human cells |
| Organisation | Laval University Cancer Research Center |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | My team discovered a new factor in human cells which controls the choice between the different modes of double strand break repair in human cells |
| Collaborator Contribution | Our collaborators measured DNA end resection rates in human cells lacking our new factor, using state-of-the-art methods they developed |
| Impact | None yet. Paper in the pipeline |
| Start Year | 2020 |
| Description | Analysis of RNA-DNA hybrid species in human cells |
| Organisation | University of Seville |
| Country | Spain |
| Sector | Academic/University |
| PI Contribution | My team discovered a new protein we identified which we discovered acts in transcription-coupled responses to DNA damage |
| Collaborator Contribution | Our collaborators at University of Seville are world leaders in the analysis of RNA-DNA hybrids in human cells. They are helping us to delineate the functions of the new protein we identified which acts in transcription-coupled responses to DNA damage |
| Impact | Too early |
| Start Year | 2022 |
| Description | Analysis of primary cilia in human cells |
| Organisation | German Cancer Research Center |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | We discovered a new regulatory subunit of the NEK1 kinase which is known to be mutated in human diseases. We have been studying if tis subunit is required for known NEK1 functions such as ciliogenesis |
| Collaborator Contribution | Our collaborators are experts in the analysis of primary cilia using advanced techniques including mass spectrometry. They are analysing the primary cilia in human cells in which we disrupted the NEK1 regulatory subunit |
| Impact | Too early |
| Start Year | 2022 |
| Description | Analysis of the SPT2 histone chaperone in C. elegans |
| Organisation | Institute for Basic Science , Korea |
| Country | Korea, Republic of |
| Sector | Academic/University |
| PI Contribution | We identified a uncharacterised C.elegans open reading frame as an orthologue of the SPT2 histone chaperone about which very little is known in eukaryotes. |
| Collaborator Contribution | Anton Gartner has helped us to delineate the function of SPT2 in worms |
| Impact | The postdoc working on it was awarded an EMBO Long Term Fellowship |
| Start Year | 2019 |
| Description | Analysis of the roles of the EXO5 nuclease in DNA repair |
| Organisation | University of Dundee |
| Department | School of Life Sciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Cell biological analysis of the uncharacterized nuclease EXO5 in DNA repair |
| Collaborator Contribution | Biochemical analysis of the uncharacterized nuclease EXO5 in DNA repair |
| Impact | None yet |
| Start Year | 2017 |
| Description | Characterization of CDKL5 signalling in brain |
| Organisation | University of Edinburgh |
| Department | School of Chemistry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Providing data on how CDKL5 signals inside cells |
| Collaborator Contribution | Analysis of CDKL5 signaling in brain in vivo and advanced imaging relevant to these experiments |
| Impact | None yet |
| Start Year | 2015 |
| Description | Characterization of SCAF1a new genome maintenance factor |
| Organisation | Oncode Institute |
| Country | Netherlands |
| Sector | Academic/University |
| PI Contribution | Discovery of SCAF1 as a new genome maintenance factor |
| Collaborator Contribution | PARP inhibitor sensitivity assays |
| Impact | paper in preparation |
| Start Year | 2022 |
| Description | Characterization of new drugs targets involved in DNA repair |
| Organisation | Merck |
| Country | Germany |
| Sector | Private |
| PI Contribution | We are helping Merck to investigate new drug targets in the DNA repair arena, and helping characterize new inhibitors of DNA repair. |
| Collaborator Contribution | Merck provide advice and compounds and use the data generated in my lab to refine their drug programmes. The funds they provided fund three postdocs in my lab |
| Impact | None yet |
| Start Year | 2016 |
| Description | Correlating the severity of disease symtoms caused by mutations in the CDKL5 kinase and impact on kinase activity |
| Organisation | Telethon Kids Institute |
| Country | Australia |
| Sector | Charity/Non Profit |
| PI Contribution | We have developed the first assays for montoring the activity of the CDKL5 kinase in cells and in vitro. Historically, CDKL5 mutations were known to cause CDKL5 deficiency disorder (CDD). CDD is a severe condition, accompanied by seizures, profound developmental delay, rmental retardation, and visual impairment. Recently, patients were identified intellectual disability without seizures, and with autism. We showed that the CDKL5 mutations in these patients reduce CDKL5 kinase activity but the effect was much less profound than the CDD-associated mutations. |
| Collaborator Contribution | Our collaborator identified the patients in which the symptoms caused by CDKL5 mutations are milder than CDD |
| Impact | A landmark paper: DOI: 10.1002/ajmg.a.61504 |
| Start Year | 2019 |
| Description | Defining the roles of C15ORF41 in health and disease |
| Organisation | University of Oxford |
| Department | Weatherall Institute of Molecular Medicine (WIMM) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Cell biological analysis of the C15ORF41 nuclease mutated in CDAI-type congential anemia |
| Collaborator Contribution | Biochemical analysis of the C15ORF41 nuclease mutated in CDAI-type congential anemia |
| Impact | None yet |
| Start Year | 2016 |
| Description | Determining how mutations in the CDKL5 kinase cause the symptoms associated with CDKL5 deficiency |
| Organisation | Loulou Foundation |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | We are studying how CDKL5 mutations affect CDKL5 activity and substrate phosphorylation. |
| Collaborator Contribution | Loulou Foundation keeps us in contact with other CDKL5 researchers through the CDKL5 Fourm and Portal and with patients and parents |
| Impact | None yet |
| Start Year | 2016 |
| Description | Expansion imaging of CDKL5 activity in brain |
| Organisation | Massachusetts Institute of Technology |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | We will provide antibodies against CDKL5 and substrates for imaging |
| Collaborator Contribution | Our collaborator will help with revolutionary new technology he developed |
| Impact | None yet |
| Start Year | 2017 |
| Description | Functional characterization of the SPT2 histone chaperone in metazoans |
| Organisation | University of Cambridge |
| Department | Department of Biochemistry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Discovery that SPT2 is involved in nuclear RNAi pathways |
| Collaborator Contribution | Gene silencing assay |
| Impact | Paper under review |
| Start Year | 2021 |
| Description | Functional characterization of the SPT2 histone chaperone in metazoans |
| Organisation | University of Cambridge |
| Department | Gurdon Institute |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | First evidence that SPT-2 is important for chromatin preservation in metazoans |
| Collaborator Contribution | Collaboration on ChIP technologies |
| Impact | Paper under review |
| Start Year | 2022 |
| Description | Generation of ALS-associated mutations in NEK1 and C21ORF2 in ALS |
| Organisation | University of Edinburgh |
| Department | Centre for Clinical Brain Sciences (CCBS) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | My lab has identified the first physiological substrates of the NEK1 kinase mutated in several diseases including amyotrophic lateral sclerosis. We would like to test the phopshorylation of these substrates in human iPS cells, and the collaboration will enable us to do this. We will make iPSC harboring ALS-associated NEK1 mutations and test the impact on substrate phosphorylation |
| Collaborator Contribution | Our collaborator has the expertise necessary to carry out genome editing of human iPSC |
| Impact | None yet but there are 3 grant applications in the pipeline |
| Start Year | 2019 |
| Description | Identification of CDKL5 substrates |
| Organisation | Dundee Model Railway Club |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Follow up of the substrates of CDKL5 identified by collaborator |
| Collaborator Contribution | Identification of CDKL5 substrates |
| Impact | None yet - multiple outputs anticipated |
| Start Year | 2016 |
| Description | Identification of the substrates of the FBXO16-SCF E3 ubiquitin ligase |
| Organisation | Harvard University |
| Department | Harvard Medical School |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | We identified FBXO16 is a screen for DNA damage-reponsive F-box proteins. These are the substrate adaptor subunits of SCF-type E3 ubiquitin ligases. We generated FBXO16 knockout human cells using genome editing. |
| Collaborator Contribution | Our collaborator is applying state-of-the-art technologies developed in their lab to identify the substrates of FBXO16 |
| Impact | None yet |
| Start Year | 2019 |
| Description | Investigating kinase function in promoting transcriptional elongation |
| Organisation | University of Copenhagen |
| Department | Biotech Research and Innovation Center (BRIC) |
| Country | Denmark |
| Sector | Academic/University |
| PI Contribution | We identified kinases mutated in human diseases which control transcriptional elongation in human cells |
| Collaborator Contribution | Collaborators carried out genome wide analysis of transcriptional elongation rates in cells lacking kinases we are working on |
| Impact | None yet. Paper in the pipeline |
| Start Year | 2020 |
| Description | Regulation of the SLX4 complex |
| Organisation | University of Toronto |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | Reagents, expertise and experimental data relating to the SLX4 complex |
| Collaborator Contribution | Reagents, expertise and experimental data relating to the SLX4 complex |
| Impact | None yet; several papers anticipated |
| Start Year | 2018 |
| Description | Role of the Ankle1 nuclease in maintaining genome stability |
| Organisation | University of Vienna |
| Department | Max F. Perutz Laboratories (MFPL) |
| Country | Austria |
| Sector | Academic/University |
| PI Contribution | We are crossing Ankle null mice to our Slx1 null mice to see if the synthetic lethality we observed in worms hold true in mammals |
| Collaborator Contribution | Our collaborators made the Ankle null mice |
| Impact | None yet |
| Start Year | 2016 |
| Description | Role of the CDKL5 kinase in DNA repair and human health |
| Organisation | University of Sussex |
| Department | Genome Damage and Stability Centre |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Biochemical analysis of CDKL5 in DNA repair and effect of pathological mutations |
| Collaborator Contribution | Cell biological analysis of CDKL5 in DNA repair and effect of pathological mutations |
| Impact | None yet |
| Start Year | 2018 |
| Description | The role of NEK1 in homologous recombination |
| Organisation | Mount Sinai Hospital (Canada) |
| Department | Lunenfeld-Tanenbaum Research Institute |
| Country | Canada |
| Sector | Hospitals |
| PI Contribution | We discovered a regulatory subunit of the NEK1 kinase which is thought to regulate the homologous recombination mode of DNA repair. |
| Collaborator Contribution | Using specialised technologies our collaborator showed that disrupting the NEK1 regulatory subunit causes the same loss of HR as seen in NEk1-deficient cells |
| Impact | Too early |
| Start Year | 2021 |
| Description | Using nematodes to Investigate the function of a novel metazoan histone chaperone |
| Organisation | University of Cambridge |
| Department | Gurdon Institute |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | My team discovered a novel histone chaperone in metazoans, and we collaborate with nematode specialists in Cambridge to study the role of histone recycling by this chaperone in a biological context |
| Collaborator Contribution | My team discovered a novel histone chaperone in metazoans, and we collaborate with nematode specialists in Cambridge to study the role of histone recycling by this chaperone in a biological context |
| Impact | None yet. Paper in the pipeline |
| Start Year | 2020 |
| Description | Validation of new drug targets in the DNA repair arena |
| Organisation | Pfizer Inc |
| Department | Biotherapeutics Division |
| Country | United States |
| Sector | Private |
| PI Contribution | Pfizer have funded two postdoctoral positions in my lab for collaborative projects exploring new drug targets relevant to our work |
| Collaborator Contribution | Pfizer have funded two postdoctoral positions in my lab for collaborative projects exploring new drug targets relevant to our work |
| Impact | None yet |
| Start Year | 2021 |
| Description | Discussion with undergraduate medical students about the value of biomedical research |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Undergraduate students |
| Results and Impact | Myself and three other group leaders hosted an evening for almost 50 medical school undergraduates. This even was organised in response to a request from the students to learn about the disease-relevant research activities in the MRC Protein Phosphorylation and Ubiquitylation Unit an d the relationship between basic research, drug target identification and drug discovery. After talks from group leaders, students were free to speak with group leaders informally at a reception. There is a real shortage of clinicians in research positions, and after the event, several students expressed the desire to carry out summer placements, project placements and MSc projects in our Unit. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Engagement with the parents of children with CDKL5 deficiency disorder |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | I have extensive interaction with several patient/parent groups relating to CDKL5 deficiency disorder (CDD). I have presented in lay-terms the main findings of out research on the molecular mechanisms underlying CDD, and explained how we hope the make tools that will allow us to carry out functional screen to effect the "molecular rebalancing" of CDD. This would represent the first attempt to treat the cause, as opposed to the symptoms, of CDD. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Open evening for medical students to showcase biomedical research in Dundee |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Undergraduate students |
| Results and Impact | Myself and a number of colleagues, which included to consultant neurologists who are also academic researchers, hosted an open evening for medical students at Dundeeand St Andrews Universities. This event featured talks from researchers investigating molecular mechanisms underlying human diseases. Talks were followed by Q&A session and a mingle. The idea was to encourage the medical students to consider engaging in scientific research, and doing a PhD in biomedical science. The two consultant were able to discuss how best to do this, in terms of timing, and how they balance clinical and non-clinical committments. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Panel discussion about the importance of basic research |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | I was part of an expert panel in a Q and A session at which undergraduate and postgraduates could ask any question about life as a research scientist, and explore views on gender equality, mental health and work/life balance. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Presentation and discussion with Members of Scottish Parliament (MSP) |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Policymakers/politicians |
| Results and Impact | Three of us my our Unit attended an event at the Scottish Parliament. showcase the work of the Medical Research Council (MRC) in Scotland, bringing together researchers based across the country into one place to talk with MSPs and other sector stakeholders about their work, the impact it is having in Scotland, the UK and beyond. At the event MSPs, key government officials and other sector stakeholders explored different exhibition stalls and spoke to researchers to learn about the impact of their work. I interacted with several MSPs to tell them about our research and our aims and activities and those of MRC and UKRI. We had a poster explaining our research and pamphlets which I gave to various MSPs. Lewis Macdonald MSP hosted the event Professor Fiona Watt, MRC Executive Chair, were present and both of them gave speeches. The event provided an opportunity to increase understanding amongst MSPs of the MRC's strategic vision and the leading role it plays in improving human health, innovation and economic growth by seeing first-hand the research that is taking place and the researchers that make it happen. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Presentation to parents of children with CDKL5 Deficiency Disorder |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | I participated in the 2018 CDKL5 Forum at the Crick Institute, driven by the Loulou Foundation, London which aims to accelerate the discovery of cures for CDKL5 deficiency disorder (CDD). The audience had parents of the sick children, pharmaceutical and biotech industry representatives, scientists and the founders and trustees of Loulou Foundation. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Promotional video for Loulou Foundation |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Supporters |
| Results and Impact | Promotional video as a scientist funded by Loulou |
| Year(s) Of Engagement Activity | 2017 |
| Description | School visit (Waterford) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Schools |
| Results and Impact | I gave a presentation to 6th year secondary school kids on the life of a research scientist |
| Year(s) Of Engagement Activity | 2019 |
| Description | Talk at school |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Talked with around 50 final year secondary school children about life as a research scientist |
| Year(s) Of Engagement Activity | 2017 |
| Description | Visit to Scottish Parliament to engage with MSPs and discuss Life Sciences Research in Scotland |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Policymakers/politicians |
| Results and Impact | A group of MRC-funded researchers from out Unit travelled to the Scottish Parliament for an evening to mix with MSPs interested in finding out about Life Sciences in Scotland. Fiona Watt, head of the MRC, gave a talk outlining MRC activities in Scotland. I spoke with a number of politicians, and discussed the strengths of research in Scotland. I also outlined challenges that lie ahead, and emphasized the links between strong academic research and the identification of new drug targets in important diseases. |
| Year(s) Of Engagement Activity | 2019 |