14CONFAP Understanding diverged genome repair and replication functions in trypanosomatid parasites
Lead Research Organisation:
University of Glasgow
Department Name: College of Medical, Veterinary, Life Sci
Abstract
This proposal has two overarching aims. The first aim is research-driven: we wish to understand the unusual behaviour of a a genome repair pathway termed nucleotide excision repair in two important human pathogens, Trypanosoma brucei (an African trypanosome, which is also an important animal pathogen) and Trypanosoma cruzi (a major parasite in South and Central America). Our rationale for this research is based on previous studies in T. brucei, which have suggested that the nucleotide excision repair machinery that acts to protect the parasite's genome from various forms of damage may have a different composition from what has been described in other organisms, including humans, and that some of the predicted machinery may in fact provide a different (and at the moment unknown) function in the cell. Currently, it is easier and quicker to do genetic experiments in T. brucei than in T. cruzi, and we will pioneer the nucleotide excision repair studies in the former and extend this work to the American trypanosome. In the second aim, we wish to run a residential meeting in Brazil on parasite genome repair and replication, with the purpose of fostering greater long-term links between Brazil and UK researchers in this area.
Technical Summary
This proposal has two overarching aims. The first aim is research-driven: we wish to understand streamlining and neo-functionalisation we described in a genome repair pathway termed nucleotide excision repair (NER) in T. brucei, and to extend this work to the American trypanosomatid parasite T. cruzi. In the second aim, we wish to run a residential meeting in Brazil on parasite genome repair and replication, with the purpose of fostering greater long-term links between Brazil and UK researchers in this area. In terms of research, we will puruse a number of questions. First, using next generation sequencing, we will test the role of nucleotide excision repair factors in the maintenance of multigenic transcription in the African trypanosome, Trypanosoma brucei. Second, using microscopic and single molecule analysis, we will ask whether or not essential nucleotide excision repair factors contribute to nuclear or mitochondrial genome replication in T. brucei. Third, we will extend any findings regarding T. brucei nucleotide excision repair functions to T. cruzi, thus asking if they are conserved or diverged in the American trypanosome. Finally, to attempt to contribute to more rapid genetic analysis in T.cruzi, we will test the feasibility of DiCre-mediated genetic manipulation in this organism. To realise the second aim, we will run a residential meeting on parasite genome replication and repair in Belo Horizonte, Brazil, allowing the immediate exchange of ideas and resources, leading to the establishment a long-term parasite genome stability research network involving intra-Brazil and Brazil-UK collaborations.
Planned Impact
N/A
Organisations
- University of Glasgow (Lead Research Organisation)
- UNIVERSITY OF EDINBURGH (Collaboration)
- Federal University of Minas Gerais (Collaboration)
- Fundação de Amparo à Pesquisa do Estado de Minas Gerais (Collaboration)
- UNIVERSITY OF LIVERPOOL (Collaboration)
- Universidade Federal de Minas Gerais (Project Partner)
Publications
Briggs EM
(2020)
Next-Generation Analysis of Trypanosomatid Genome Stability and Instability.
in Methods in molecular biology (Clifton, N.J.)
Briggs E
(2018)
Ribonuclease H1-targeted R-loops in surface antigen gene expression sites can direct trypanosome immune evasion.
in PLoS genetics
Briggs E
(2018)
Genome-wide mapping reveals conserved and diverged R-loop activities in the unusual genetic landscape of the African trypanosome genome.
in Nucleic acids research
Briggs E
(2019)
Trypanosoma brucei ribonuclease H2A is an essential R-loop processing enzyme whose loss causes DNA damage during transcription initiation and antigenic variation.
in Nucleic acids research
Black JA
(2023)
AAK1-like: A putative pseudokinase with potential roles in cargo uptake in bloodstream form Trypanosoma brucei parasites.
in The Journal of eukaryotic microbiology
Almeida LV
(2018)
Chromosomal copy number variation analysis by next generation sequencing confirms ploidy stability in Trypanosoma brucei subspecies.
in Microbial genomics
Description | Description of novel use of nucleotide excision repair |
Exploitation Route | Provided materials to collaborators in Brazil and in QMUL, UK. |
Sectors | Education,Pharmaceuticals and Medical Biotechnology,Other |
Description | A distinct mode of DNA replication initiation in trypanosomes? |
Amount | £756,872 (GBP) |
Funding ID | BB/W001101/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2022 |
End | 09/2025 |
Description | Challenging trypanosome antigenic variation paradigms using natural systems |
Amount | £2,070,288 (GBP) |
Funding ID | 206815/Z/17/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2018 |
End | 01/2024 |
Description | FAPESP-Glasgow University Sprint |
Amount | £20,000 (GBP) |
Organisation | São Paulo Research Foundation (FAPESP) |
Sector | Public |
Country | Brazil |
Start | 05/2017 |
End | 05/2019 |
Description | MRC Precision Medicine PhD project |
Amount | £100,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2018 |
End | 10/2022 |
Description | Science Without Borders |
Amount | £60,000 (GBP) |
Organisation | Government of Brazil |
Department | Coordination of Higher Education Personnel Training (CAPES) |
Sector | Public |
Country | Brazil |
Start | 11/2015 |
End | 11/2016 |
Description | Wellcome Investigator Award |
Amount | £1,655,328 (GBP) |
Funding ID | 224501/Z/21/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2022 |
End | 07/2027 |
Title | Mapping replication origins in two Leishmania species |
Description | MFAseq of origins in L. major and L. mexicana |
Type Of Material | Technology assay or reagent |
Year Produced | 2015 |
Provided To Others? | Yes |
Impact | publication; data available via tritrypdb |
URL | http://tritrypdb.org |
Title | RNAi of repair factors in T. brucei |
Description | Sequence data of effect of RNAi in the presence of DNA damage |
Type Of Material | Database/Collection of data |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | Data to guide future research |
Title | gammaH2A in T. brucei |
Description | Sequence data of localisation of modified histone |
Type Of Material | Database/Collection of data |
Year Produced | 2018 |
Provided To Others? | No |
Impact | Guide future research when published |
Description | DNA metabolism in trypanosomatids: state of art and future directions |
Organisation | FAPEMIG |
Country | Brazil |
Sector | Private |
PI Contribution | Co-organisation of symposium on trypanosomatid DNA metabolism; talks by all current post-docs and PhD students |
Collaborator Contribution | Co-organisation of symposium on trypanosomatid DNA metabolism; talks by all current post-docs and PhD students |
Impact | Collaboration and knowledge exchange |
Start Year | 2015 |
Description | Joint Wellcome Trust collaboratiev award |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Writing and securing award; foundation data in support of the award |
Collaborator Contribution | Writing and securing award; foundation data in support of the award |
Impact | None to date |
Start Year | 2018 |
Description | Joint Wellcome Trust collaboratiev award |
Organisation | University of Liverpool |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Writing and securing award; foundation data in support of the award |
Collaborator Contribution | Writing and securing award; foundation data in support of the award |
Impact | None to date |
Start Year | 2018 |
Description | Visiting professor, Federal University Of Minas Gerais |
Organisation | Federal University of Minas Gerais |
Country | Brazil |
Sector | Academic/University |
PI Contribution | Formal arrangement, funded by CAPES Print programme, for me to visit UFMG and teach and develop ongoing research collaborations; established after British Council-funded visit to UFMG in November 2018 |
Collaborator Contribution | Colleagues in UFMG applied for an received Print funding for the collaboration |
Impact | Exchange of teaching expertise, improved research collaboration |
Start Year | 2020 |
Description | Glasgow Science Week |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Hands on research experience for near school leavers thinking about attending university |
Year(s) Of Engagement Activity | 2018 |
Description | Meeting between Glasgow University and Federal University of Minas Gerais |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Policymakers/politicians |
Results and Impact | A week of discussion meetings to determine future directions of collaborations between the UK and Brazil institutions |
Year(s) Of Engagement Activity | 2017 |
Description | Meeting between University fo Glasgow and Federal University of Minas Gerais |
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 | Meeting to consider presence of University of Glasgow in upcoming UFM Print award for staff mobility. |
Year(s) Of Engagement Activity | 2018 |
Description | Pathogen investigation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | A series of experiments for secondary school pupils who are pursuing their highers and considering whether or not to apply for university. The pupils were given a short talk on pathogen biology and then conducted a series of pre-arranged experiments to gain insight into how science is pursued. |
Year(s) Of Engagement Activity | 2013,2014,2015,2016,2017 |
Description | Secondary school visit |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Secondary school pupils visited the host laboratory and were allowed to conduct controlled experiments and view ongoing experiments. |
Year(s) Of Engagement Activity | 2013,2014,2015,2016,2017 |
Description | Visiting local school |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Visit to local school to discuss microbiology |
Year(s) Of Engagement Activity | 2018 |
Description | hosting visiting school |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | hosting local school, hands-on 'taster' activities in science |
Year(s) Of Engagement Activity | 2017 |
Description | open day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Open day to provide information on degrees at Glasgow University |
Year(s) Of Engagement Activity | 2017 |