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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Evaluation of mechanisms that may generate DNA lesions triggering antigenic variation in African trypanosomes

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Autor(es):
da Silva, Marcelo Santos [1, 2] ; Hovel-Miner, Galadriel A. [3] ; Briggs, Emma M. [1] ; Elias, Maria Carolina [2] ; Mcculloch, Richard [1]
Número total de Autores: 5
Afiliação do(s) autor(es):
[1] Univ Glasgow, Inst Infect Immun & Inflammat, Wellcome Ctr Mol Parasitol, Glasgow, Lanark - Scotland
[2] Inst Butantan, Ctr Toxins Immune Response & Cell Signaling CeTIC, Lab Especial Ciclo Celular, Sao Paulo - Brazil
[3] George Washington Univ, Dept microbiol Immunol & Trop Med, Washington, DC - USA
Número total de Afiliações: 3
Tipo de documento: Artigo de Revisão
Fonte: PLOS PATHOGENS; v. 14, n. 11 NOV 2018.
Citações Web of Science: 1
Resumo

Antigenic variation by variant surface glycoprotein (VSG) coat switching in African trypano-somes is one of the most elaborate immune evasion strategies found among pathogens. Changes in the identity of the transcribed VSG gene, which is always flanked by 70-bp and telomeric repeats, can be achieved either by transcriptional or DNA recombination mechanisms. The major route of VSG switching is DNA recombination, which occurs in the bloodstream VSG expression site (ES), a multigenic site transcribed by RNA polymerase I. Recombinogenic VSG switching is frequently catalyzed by homologous recombination (HR), a reaction normally triggered by DNA breaks. However, a clear understanding of how such breaks arise-including whether there is a dedicated and ES-focused mechanism-is lacking. Here, we synthesize data emerging from recent studies that have proposed a range of mechanisms that could generate these breaks: action of a nuclease or nucleases; repetitive DNA, most notably the 70-bp repeats, providing an intra-ES source of instability; DNA breaks derived from the VSG-adjacent telomere; DNA breaks arising from high transcription levels at the active ES; and DNA lesions arising from replication-transcription conflicts in the ES. We discuss the evidence that underpins these switch-initiation models and consider what features and mechanisms might be shared or might allow the models to be tested further. Evaluation of all these models highlights that we still have much to learn about the earliest acting step in VSG switching, which may have the greatest potential for therapeutic intervention in order to undermine the key reaction used by trypanosomes for their survival and propagation in the mammalian host. (AU)

Processo FAPESP: 13/07467-1 - CeTICS - Centro de Toxinas, Imuno-Resposta e Sinalização Celular
Beneficiário:Hugo Aguirre Armelin
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 14/24170-5 - Dinâmica da replicação do DNA em Trypanosoma cruzi: caracterização do licenciamento e da taxa de replicação
Beneficiário:Marcelo Santos da Silva
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 16/50050-2 - How do common and diverged features of the replicative stress response shape the biology of TriTryp parasites?
Beneficiário:Maria Carolina Quartim Barbosa Elias Sabbaga
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 17/18719-2 - Análise estrutural do complexo de reconhecimento de origens de replicação (ORC) em Trypanosoma brucei utilizando cryo-electron microscopy e single-particle analysis
Beneficiário:Marcelo Santos da Silva
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado