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Here, we characterize a\n                    <jats:italic>T. brucei<\/jats:italic>\n                    cytidine deaminase-like protein (TbCDA-like), a kinetoplastid-specific enzyme absent in mammals, that harbors a deaminase domain and a zinc-finger CCCH motif. Using RNA interference (RNAi) and overexpression approaches, we demonstrate that TbCDA-like modulates pyrimidine nucleotide pools, influencing both ribonucleotide and deoxyribonucleotide profiles. Overexpression of TbCDA-like resulted in a substantial reduction of dCTP and CTP levels while elevating dTTP and UTP pools, suggesting a role in cytidine derivative deamination. Conversely, RNAi-mediated depletion of TbCDA-like caused CMP accumulation and reduced dTTP levels. Notably, overexpression induced severe cytotoxicity, growth arrest, DNA damage and cell cycle defects, evidenced by sub-G1 populations, increased nuclear H2A phosphorylation and aberrant kinetoplast and nuclear morphologies. Localization studies revealed that TbCDA-like is primarily cytosolic and relocalizes to stress granules upon nutrient deprivation, suggesting a role in RNA metabolism. These findings establish TbCDA-like as a key regulator of pyrimidine nucleotide homeostasis in\n                    <jats:italic>T. brucei<\/jats:italic>\n                    , linking nucleotide imbalances to DNA replication stress and genome instability. Given its absence in mammals, TbCDA-like presents an attractive target for therapeutic intervention against trypanosomiasis.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-00942-2","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T23:44:48Z","timestamp":1746747888000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A cytidine deaminase-like protein modulates pyrimidine nucleotide homeostasis in Trypanosoma brucei"],"prefix":"10.1038","volume":"15","author":[{"given":"Ana","family":"Moro-Bulnes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Bosch-Navarrete","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo","family":"Antequera-Parrilla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Santiago","family":"Castanys","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio E.","family":"Vidal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis Miguel","family":"Ruiz-P\u00e9rez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guiomar","family":"P\u00e9rez-Moreno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dolores","family":"Gonz\u00e1lez-Pacanowska","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"942_CR1","doi-asserted-by":"publisher","first-page":"1037094","DOI":"10.3389\/fmed.2022.1037094","volume":"9","author":"A \u00c1lvarez-Rodr\u00edguez","year":"2022","unstructured":"\u00c1lvarez-Rodr\u00edguez, A., Jin, B. K., Radwanska, M. & Magez, S. Recent progress in diagnosis and treatment of human African trypanosomiasis has made the elimination of this disease a realistic target by 2030. Front. Med. 9, 1037094. https:\/\/doi.org\/10.3389\/fmed.2022.1037094 (2022).","journal-title":"Front. Med."},{"key":"942_CR2","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1146\/annurev-pathmechdis-031621-025153","volume":"18","author":"E Pays","year":"2023","unstructured":"Pays, E., Radwanska, M. & Magez, S. The pathogenesis of African trypanosomiasis. Annu. Rev. Pathol. 18, 19\u201345. https:\/\/doi.org\/10.1146\/annurev-pathmechdis-031621-025153 (2023).","journal-title":"Annu. Rev. Pathol."},{"key":"942_CR3","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1186\/s13071-018-2660-8","volume":"11","author":"K Tiwari","year":"2018","unstructured":"Tiwari, K. & Dubey, V. K. Fresh insights into the pyrimidine metabolism in the trypanosomatids. Parasit. 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