The in vivo and in vitro roles of Trypanosoma cruzi Rad51 in the repair of DNA double strand breaks and oxidative lesions

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Passos Silva, Danielle Gomes ^[1] ; Santos, Selma da Silva ^{[2, 1]} ; Nardelli, Sheila C. ^[3] ; Mendes, Isabela Cecilia ^[1] ; Guimaraes Freire, Anna Claudia ^[1] ; Repoles, Bruno Marcal ^[1] ; Resende, Bruno Carvalho ^[1] ; Costa-Silva, Hellida Marina ^[1] ; da Silva, Veronica Santana ^[1] ; de Oliveira, Karla Andrade ^[1] ; Batista Oliveira, Camila Franco ^[1] ; Felicori Vilela, Liza Figueiredo ^[1] ; Pinto Nagem, Ronaldo Alves ^[1] ; Franco, Gloria Regina ^[1] ; Macedo, Andrea Mara ^[1] ; Junho Pena, Sergio Danilo ^[1] ; Tahara, Erich Birelli ^[1] ; Sales Junior, Policarpo Ademar ^[2] ; Moreira, Douglas Souza ^[2] ; Ribeiro Teixeira, Santuza Maria ^[1] ; McCulloch, Richard ^[4] ; Virgilio, Stela ^[5] ; Orsini Tosi, Luiz Ricardo ^[5] ; Schenkman, Sergio ^[6] ; Andrade, Luciana Oliveira ^[7] ; Fonseca Murta, Silvane Maria ^[2] ; Machado, Carlos Renato ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Minas Gerais, Dept Bioquim & Imunol, ICB, Belo Horizonte, MG - Brazil

^[2] Fiocruz MS, Ctr Pesquisas Rene Rachou, Belo Horizonte, MG - Brazil

^[3] Fiocruz MS, Inst Carlos Chagas, Rua Prof Algacyr Munhoz Mader 3775, Curitiba, Parana - Brazil

^[4] Univ Glasgow, Wellcome Trust Ctr Mol Parasitol, Glasgow Biomed Res Ctr, Glasgow, Lanark - Scotland

^[5] Univ Sao Paulo, Dept Cell & Mol Biol, Ribeirao Preto Med Sch, Ribeirao Preto, SP - Brazil

^[6] Univ Fed Sao Paulo, Dept Microbiol Imunol & Parasitol, Rua Pedro de Toledo 669, Sao Paulo, SP - Brazil

^[7] Univ Fed Minas Gerais, ICB, Dept Morfol, Caixa Postal 486, Belo Horizonte, MG - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS Neglected Tropical Diseases; v. 12, n. 11 NOV 2018.
• Citações Web of Science: 3

Resumo

In Trypanosoma cruzi, the etiologic agent of Chagas disease, Rad51 (TcRad51) is a central enzyme for homologous recombination. Here we describe the different roles of TcRad51 in DNA repair. Epimastigotes of T. cruzi overexpressing TcRAD51 presented abundant TcRad51-labeled foci before gamma irradiation treatment, and a faster growth recovery when compared to single-knockout epimastigotes for RAD51. Overexpression of RAD51 also promoted increased resistance against hydrogen peroxide treatment, while the single-knockout epimastigotes for RAD51 exhibited increased sensitivity to this oxidant agent, which indicates a role for this gene in the repair of DNA oxidative lesions. In contrast, TcRad51 was not involved in the repair of crosslink lesions promoted by UV light and cisplatin treatment. Also, RAD51 single-knockout epimastigotes showed a similar growth rate to that exhibited by wild-type ones after treatment with hydroxyurea, but an increased sensitivity to methyl methane sulfonate. Besides its role in epimastigotes, TcRad51 is also important during mammalian infection, as shown by increased detection of T. cruzi cells overexpressing RAD51, and decreased detection of single-knockout cells for RAD51, in both fibroblasts and macrophages infected with amastigotes. Besides that, RAD51-overexpressing parasites infecting mice also presented increased infectivity and higher resistance against benznidazole. We thus show that TcRad51 is involved in the repair of DNA double strands breaks and oxidative lesions in two different T. cruzi developmental stages, possibly playing an important role in the infectivity of this parasite. (AU)

• Processo FAPESP: 17/07092-9 - Como as proteínas de checkpoint Rad9 e Hus1 atuam na manutenção da estabilidade do genoma do protozoário Leishmania major?
• Beneficiário: Luiz Ricardo Orsini Tosi
• Modalidade de apoio: Auxílio à Pesquisa - Regular