14CONFAP Understanding diverged genome repair and replication functions in trypanosomatid parasites

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.

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.

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