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Are devolved functions of components of the 9-1-1 complex a common feature of TriTryp genome biology?

Processo: 16/50193-8
Linha de fomento:Auxílio à Pesquisa - Regular
Vigência: 01 de novembro de 2016 - 31 de outubro de 2019
Área do conhecimento:Ciências Biológicas - Parasitologia - Protozoologia de Parasitos
Convênio/Acordo: University of Glasgow
Pesquisador responsável:Luiz Ricardo Orsini Tosi
Beneficiário:Luiz Ricardo Orsini Tosi
Pesq. responsável no exterior: Richard Mcculloch
Instituição no exterior: University of Glasgow, Escócia
Instituição-sede: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brasil
Assunto(s):Leishmania  Trypanosoma  Genomas  Análise de sequência de DNA  Sequenciamento de nova geração 


Recent work in Leishmania examined a key player in the damage sensing, cell cycle progression and DNA repair processes in these organisms. This factor, termed the Rad9-Rad1-Hus1 (9-1-1) complex is a ring-shaped heterotrimeric complex, structurally related to the PCNA clamp and is conserved amongst eukaryotes. Accumulating evidence indicates Leishmania 9-1-1 is central to genome maintenance and has evolved by a distinct route: devolution of both Rad9 and Hus1 activities. Gene knockout attempts have suggested that Rad9 and Hus1 are essential and cells deficient for either Rad9 or Hus1 display contrasting phenotypes when exposed to a range of genotoxic damage. In this project we wish to further study 9-1-1 functions by comparing Leishmania and T. brucei. It will be informative to ask if the devolved functions of Rad9 and Hus 1, as well as the core genome maintenance functions of 9-1-1, act to cope with the unusual biology of the Leishmania genome, or if they are seen also in T. brucei, which is (in some regards) more conventionally like other eukaryotes. We will use established biochemical approaches to ask if the devolved interactions of Rad9 and Hus1 seen in Leishmania are also found in T. brucei. We will apply genome-wide next generation sequencing strategies, in both parasites, to evaluate the impact of loss of the factors on genome replication and stability, and we will adapt the established iPOND strategy for use in the parasites allowing us to more clearly define all factors acting at replication forks. (AU)