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Artículo

Essential Bromodomain TcBDF2 as a Drug Target against Chagas Disease

Pezza, AlejandroIcon ; Tavernelli, Luis EmilioIcon ; Alonso, Victoria LuciaIcon ; Perdomo, VirginiaIcon ; Gabarro, Raquel; Prinjha, Rab; Rodríguez Araya, ElvioIcon ; Rioja, Inmaculada; Docampo, Roberto; Calderón, Felix; Martin, Julio; Serra, Esteban CarlosIcon
Fecha de publicación: 04/2022
Editorial: American Chemical Society
Revista: ACS Infectious Diseases
ISSN: 2373-8227
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Bioquímica y Biología Molecular

Resumen

Trypanosoma cruzi is a unicellular parasite that causes Chagas disease, which is endemic in the American continent but also worldwide, distributed by migratory movements. A striking feature of trypanosomatids is the polycistronic transcription associated with post-transcriptional mechanisms that regulate the levels of translatable mRNA. In this context, epigenetic regulatory mechanisms have been revealed to be of great importance, since they are the only ones that would control the access of RNA polymerases to chromatin. Bromodomains are epigenetic protein readers that recognize and specifically bind to acetylated lysine residues, mostly at histone proteins. There are seven coding sequences for BD-containing proteins in trypanosomatids, named TcBDF1 to TcBDF7, and a putative new protein containing a bromodomain was recently described. Using the Tet-regulated overexpression plasmid pTcINDEX-GW and CRISPR/Cas9 genome editing, we were able to demonstrate the essentiality of TcBDF2 in T. cruzi. This bromodomain is located in the nucleus, through a bipartite nuclear localization signal. TcBDF2 was shown to be important for host cell invasion, amastigote replication, and differentiation from amastigotes to trypomastigotes. Overexpression of TcBDF2 diminished epimastigote replication. Also, some processes involved in pathogenesis were altered in these parasites, such as infection of mammalian cells, replication of amastigotes, and the number of trypomastigotes released from host cells. In in vitro studies, TcBDF2 was also able to bind inhibitors showing a specificity profile different from that of the previously characterized TcBDF3. These results point to TcBDF2 as a druggable target against T. cruzi.
Palabras clave: BROMODOMAIN , CHAGAS DISEASE , DRUG TARGET , T. CRUZI , TRYPANOSOMATIDS
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info:eu-repo/semantics/restrictedAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/213376
URL: https://pubs.acs.org/doi/10.1021/acsinfecdis.2c00057?ref=PDF
DOI: https://doi.org/10.1021/acsinfecdis.2c00057
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Articulos(IBR)
Articulos de INST.DE BIOLOGIA MOLECULAR Y CELULAR DE ROSARIO
Citación
Pezza, Alejandro; Tavernelli, Luis Emilio; Alonso, Victoria Lucia; Perdomo, Virginia; Gabarro, Raquel; et al.; Essential Bromodomain TcBDF2 as a Drug Target against Chagas Disease; American Chemical Society; ACS Infectious Diseases; 8; 5; 4-2022; 1062-1074
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