{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T09:09:52Z","timestamp":1790500192671,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2013,12,18]],"date-time":"2013-12-18T00:00:00Z","timestamp":1387324800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Environ and Mol Mutagen"],"published-print":{"date-parts":[[2014,5]]},"abstract":"<jats:p>\n                    Benznidazole (BZ) is the most commonly used drug for the treatment of Chagas disease. Although BZ is known to induce the formation of free radicals and electrophilic metabolites within the parasite\n                    <jats:italic>Trypanosoma cruzi<\/jats:italic>\n                    , its precise mechanisms of action are still elusive. Here, we analyzed the survival of\n                    <jats:italic>T. cruzi<\/jats:italic>\n                    exposed to BZ using genetically modified parasites overexpressing different DNA repair proteins. Our results indicate that BZ induces oxidation mainly in the nucleotide pool, as heterologous expression of the nucleotide pyrophosphohydrolase MutT (but not overexpression of the glycosylase TcOgg1) increased drug resistance in the parasite. In addition, electron microscopy indicated that BZ catalyzes the formation of double\u2010stranded breaks in the parasite, as its genomic DNA undergoes extensive heterochromatin unpacking following exposure to the drug. Furthermore, the overexpression of proteins involved in the recombination\u2010mediated DNA repair increased resistance to BZ, reinforcing the idea that the drug causes double\u2010stranded breaks. Our results also show that the overexpression of mitochondrial DNA repair proteins increase parasite survival upon BZ exposure, indicating that the drug induces lesions in the mitochondrial DNA as well. These findings suggest that BZ preferentially oxidizes the nucleotide pool, and the extensive incorporation of oxidized nucleotides during DNA replication leads to potentially lethal double\u2010stranded DNA breaks in\n                    <jats:italic>T. cruzi<\/jats:italic>\n                    DNA. Environ. Mol. Mutagen. 55:309\u2013321, 2014. \u00a9 2013 Wiley Periodicals, Inc.\n                  <\/jats:p>","DOI":"10.1002\/em.21839","type":"journal-article","created":{"date-parts":[[2013,12,18]],"date-time":"2013-12-18T03:18:52Z","timestamp":1387336732000},"page":"309-321","source":"Crossref","is-referenced-by-count":94,"title":["Unveiling Benznidazole's mechanism of action through overexpression of DNA repair proteins in\n                    <i>Trypanosoma cruzi<\/i>"],"prefix":"10.1002","volume":"55","author":[{"given":"Matheus Andrade","family":"Raj\u00e3o","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica e Imunologia Instituto de Ci\u00eancias Biol\u00f3gicas, UFMG Belo Horizonte Minas Gerais"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Furtado","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica e Imunologia Instituto de Ci\u00eancias Biol\u00f3gicas, UFMG Belo Horizonte Minas 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