{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:31:14Z","timestamp":1790857874501,"version":"4.1.0"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T00:00:00Z","timestamp":1761264000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012264","name":"NIH","doi-asserted-by":"publisher","award":["P40 OD01440"],"award-info":[{"award-number":["P40 OD01440"]}],"id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003206","name":"Alberta Children\u2019s Hospital Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003206","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012866","name":"Cumming School of Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012866","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008459","name":"University of Calgary","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008459","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Dihydropyrimidine dehydrogenase (DPD), encoded by DPYD, is a key enzyme in pyrimidine catabolism, and its deficiency leads to severe toxicity in patients treated with 5-fluorouracil (5-FU). While pathogenic DPYD variants account for many cases of DPD deficiency, they do not fully explain all instances of 5-FU sensitivity, suggesting additional genetic factors are involved. Recent studies have implicated variants in CIAO1, a gene encoding a subunit of the cytosolic iron-sulfur (Fe-S) cluster assembly targeting complex, in reducing DPD stability and function. In this study, we established a C. elegans model to assess DPD deficiency and 5-FU sensitivity. Using a dpyd-1 knockout and CRISPR-generated ciao-1 variants that mirror patient-derived variants (p.Trp184Cys, p.His193Tyr, and p.Arg65Trp), we provide the first in vivo evidence that pathogenic variants in CIA complex components can lead to DPD deficiency and, consequently, heightened 5-FU toxicity. Our findings highlight the critical role of CIAO1 in DPD function and 5-FU tolerance, expanding the genetic landscape of DPD deficiency and offering a robust platform for functional evaluation of pathogenic variants.<\/jats:p>","DOI":"10.1093\/genetics\/iyaf228","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T04:16:46Z","timestamp":1761279406000},"source":"Crossref","is-referenced-by-count":1,"title":["Functional studies of human variants in\n                    <i>C. elegans<\/i>\n                    link iron metabolism to DPD deficiency and 5-FU sensitivity"],"prefix":"10.1093","volume":"232","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5372-2590","authenticated-orcid":false,"given":"Xiao","family":"Li","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary , Calgary, AB T2N 2T8 ,","place":["Canada"]},{"name":"Department of Medical Genetics, Cumming School of Medicine, University of Calgary , Calgary, AB T2N 2T8 ,","place":["Canada"]},{"name":"Alberta Children's Hospital Research Institute, University of Calgary , Calgary, AB T2N 2T8 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivette M","family":"Menendez Perdomo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary , Calgary, AB T2N 2T8 ,","place":["Canada"]},{"name":"Department of Medical Genetics, Cumming School of Medicine, University of Calgary , Calgary, AB T2N 2T8 ,","place":["Canada"]},{"name":"Alberta Children's Hospital Research Institute, University of Calgary , Calgary, AB T2N 2T8 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7989-4910","authenticated-orcid":false,"given":"Andr\u00e9 B P","family":"van Kuilenburg","sequence":"additional","affiliation":[{"name":"Amsterdam Gastroenterology Endocrinology Metabolism , Amsterdam 1105 AZ ,","place":["The Netherlands"]},{"name":"Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Amsterdam UMC, Vrije Universiteit Amsterdam , Amsterdam 1081 HV ,","place":["Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4472-8584","authenticated-orcid":false,"given":"Maja","family":"Tarailo-Graovac","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary , Calgary, AB T2N 2T8 ,","place":["Canada"]},{"name":"Department of Medical Genetics, Cumming School of Medicine, University of Calgary , Calgary, AB T2N 2T8 ,","place":["Canada"]},{"name":"Alberta Children's Hospital Research Institute, University of Calgary , Calgary, AB T2N 2T8 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,10,23]]},"reference":[{"key":"2026010708574699800_iyaf228-B1","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1534\/g3.118.200778","article-title":"Crispr\/cas9 methodology for the generation of knockout deletions in caenorhabditis elegans","volume":"9","author":"Au","year":"2019","journal-title":"G3 (Bethesda)"},{"key":"2026010708574699800_iyaf228-B2","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1093\/genetics\/77.1.71","article-title":"The genetics of caenorhabditis elegans","volume":"77","author":"Brenner","year":"1974","journal-title":"Genetics"},{"key":"2026010708574699800_iyaf228-B3","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1093\/emboj\/20.4.650","article-title":"Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil","volume":"20","author":"Dobritzsch","year":"2001","journal-title":"EMBO J."},{"key":"2026010708574699800_iyaf228-B4","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1534\/genetics.118.301532","article-title":"Robust genome editing with short single-stranded and long, partially single-stranded DNA donors in caenorhabditis elegans","volume":"210","author":"Dokshin","year":"2018","journal-title":"Genetics"},{"key":"2026010708574699800_iyaf228-B5","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/j.cell.2017.03.046","article-title":"Bacterial metabolism affects the c. 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