Estudo das acetilações na histona H4 de Trypanosoma cruzi

Detalhes bibliográficos
Ano de defesa: 2010
Autor(a) principal: Nardelli, Sheila Cristina [UNIFESP]
Orientador(a): Não Informado pela instituição
Banca de defesa: Não Informado pela instituição
Tipo de documento: Tese
Tipo de acesso: Acesso aberto
Idioma: por
Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
Programa de Pós-Graduação: Não Informado pela instituição
Departamento: Não Informado pela instituição
País: Não Informado pela instituição
Palavras-chave em Português:
Link de acesso: http://repositorio.unifesp.br/handle/11600/9540
Resumo: The Trypanosoma cruzi histones are very distinct from other eukaryotes, mainly in the N-terminus, where post translational modifications occur, which are essential for gene expression regulation and chromatin architecture. Among these modifications we found that lysines 4, 10 and 14 of H4 histone are acetylated (H4K4ac, and H4K10ac H4K14ac). In this thesis we show that the H4K4ac, which is the most abundant modification, is enriched in densely packed chromatin, while H4K10ac and H4K14ac are located in less dense chromatin, preferentially at the interface between euchromatin and heterochromatin. H4K4ac decreases in trypomastigote, which is the infective and non-dividing form of the parasite whileH4K14ac increases during G2 and mitosis of the cell cycle in replicative forms. H4K10ac and H4K14ac increases during DNA repair of double stranded breaks while H4K4ac decreases after DNA damage. TcRad51, an essential protein in the homologous recombination pathway, when overexpressed, increases the H4K10ac and H4K14ac levels. When the lysines 4, 10 and 14 are individually replaced by arginine (H4K4R, H4K10R and H4K14R) to prevent the acetylation, they are still incorporated into chromatin and decrease the specific modification level. The H4K4R location is different from the endogenous H4K4ac and the H4K14R expression causes growth reduction, with cells accumulating in mitosis. Mutants H4K10R and H4K14R also have high mortality rates after ƒ× irradiation that causes DNA double-stranded breaks. We also showed that TcBDF2 protein contains a bromodomain that recognizes preferentially H4K10ac. Although the TcBD2 function is unknown, it is increased after UV light exposure, suggesting its involvement in DNA repair. These data together provide evidence that each H4 acetylation has a distinct role in T. cruzi. Probably K4 is involved in chromatin assembly during replication while K10 and K14 acetylation appears to be involved in chromatin remodelling during DNA repair and maybe DNA transcription.