{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T22:20:33Z","timestamp":1775254833904,"version":"3.50.1"},"reference-count":28,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T00:00:00Z","timestamp":1645747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UID\/NEU\/04539\/2019"],"award-info":[{"award-number":["UID\/NEU\/04539\/2019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/ 04539\/2020"],"award-info":[{"award-number":["UIDB\/ 04539\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDP\/04539\/2020"],"award-info":[{"award-number":["UIDP\/04539\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/145531\/2019"],"award-info":[{"award-number":["SFRH\/BD\/145531\/2019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["2020.08261.BD"],"award-info":[{"award-number":["2020.08261.BD"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Genomic instability is prevented by the DNA damage response (DDR). Micronutrients, like zinc (Zn), are cofactors of DDR proteins, and micronutrient deficiencies have been related to increased cancer risk. Acute myeloid leukemia (AML) patients commonly present Zn deficiency. Moreover, reports point to DDR defects in AML. We studied the effects of Zn in DDR modulation in AML. Cell lines of AML (HEL) and normal human lymphocytes (IMC) were cultured in standard culture, Zn depletion, and supplementation (40 \u03bcM ZnSO4) conditions and exposed to hydrogen peroxide (H2O2) or ultraviolet (UV) radiation. Chromosomal damage, cell death, and nuclear division indexes (NDI) were assessed through cytokinesis-block micronucleus assay. The phosphorylated histone H2AX (yH2AX) expression was monitored at 0 h, 1 h, and 24 h after exposure. Expression of DDR genes was evaluated by quantitative real time polymerase chain reaction (qPCR). Zn supplementation increased the genotoxicity of H2O2 and UV radiation in AML cells, induced cytotoxic and antiproliferative effects, and led to persistent yH2AX activation. In contrast, in normal lymphocytes, supplementation decreased damage rates, while Zn depletion favored damage accumulation and impaired repair kinetics. Gene expression was not affected by Zn depletion or supplementation. Zn presented a dual role in the modulation of genome damage, preventing damage accumulation in normal cells and increasing genotoxicity and cytotoxicity in AML cells.<\/jats:p>","DOI":"10.3390\/ijms23052567","type":"journal-article","created":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T10:00:40Z","timestamp":1645783240000},"page":"2567","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Zinc Prevents DNA Damage in Normal Cells but Shows Genotoxic and Cytotoxic Effects in Acute Myeloid Leukemia Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Maria In\u00eas","family":"Costa","sequence":"first","affiliation":[{"name":"Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0455-4970","authenticated-orcid":false,"given":"Beatriz Santos","family":"Lapa","sequence":"additional","affiliation":[{"name":"Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0755-8077","authenticated-orcid":false,"given":"Joana","family":"Jorge","sequence":"additional","affiliation":[{"name":"Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2599-6433","authenticated-orcid":false,"given":"Raquel","family":"Alves","sequence":"additional","affiliation":[{"name":"Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal"}]},{"given":"Isabel Marques","family":"Carreira","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal"},{"name":"Cytogenetics and Genomics Laboratory, Faculty of Medicine, University of Coimbra, 3004-531 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4142-4841","authenticated-orcid":false,"given":"Ana Bela","family":"Sarmento-Ribeiro","sequence":"additional","affiliation":[{"name":"Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"Hematology Service, Centro Hospitalar e Universit\u00e1rio de Coimbra (CHUC), 3000-061 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1470-4802","authenticated-orcid":false,"given":"Ana Cristina","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.molcel.2010.09.019","article-title":"The DNA Damage Response: Making It Safe to Play with Knives","volume":"40","author":"Ciccia","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1438S","DOI":"10.3945\/ajcn.2010.28674D","article-title":"Dietary reference values of individual micronutrients and nutriomes for genome damage prevention: Current status and a road map to the future","volume":"91","author":"Fenech","year":"2010","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s00394-012-0318-4","article-title":"Effects of micronutrients on DNA repair","volume":"51","author":"Collins","year":"2012","journal-title":"Eur. J. Nutr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"632","DOI":"10.4103\/ijmr.IJMR_1738_18","article-title":"Nutrigenomics: Opportunities & challenges for public health nutrition","volume":"148","author":"Reddy","year":"2018","journal-title":"Indian J. Med. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1002\/jcb.27617","article-title":"The crosstalk between trace elements with DNA damage response, repair, and oxidative stress in cancer","volume":"120","author":"Tehrani","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_6","first-page":"676","article-title":"Zinc: A promising agent in dietary chemoprevention of cancer","volume":"132","author":"Dhawan","year":"2010","journal-title":"Indian J. Med. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s00775-018-1545-9","article-title":"The role of zinc and its compounds in leu-kemia, Journal of biological inorganic chemistry","volume":"23","author":"Orlov","year":"2018","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Skrajnowska, D., and Bobrowska-Korczak, B. (2019). Role of Zinc in Immune System and Anti-Cancer Defense Mechanisms. Nutrients, 11.","DOI":"10.3390\/nu11102273"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.jnutbio.2004.07.005","article-title":"Zinc deficiency, DNA damage and cancer risk","volume":"15","author":"Ho","year":"2004","journal-title":"J. Nutr. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1007\/s12185-017-2300-7","article-title":"The DNA damage response pathway in normal hematopoiesis and malignancies","volume":"106","author":"Delia","year":"2017","journal-title":"Int. J. Hematol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Nilles, N., and Fahrenkrog, B. (2017). Taking a Bad Turn: Compromised DNA Damage Response in Leukemia. Cells, 6.","DOI":"10.3390\/cells6020011"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"69","DOI":"10.32471\/exp-oncology.2312-8852.vol-41-no-1.12730","article-title":"Assessment of trace elements in serum of acute lymphoblastic and myeloid leukemia patients","volume":"41","author":"Valadbeigi","year":"2019","journal-title":"Exp. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.jinorgbio.2017.07.007","article-title":"PML-RARalpha stabilized by zinc in human acute promyelocytic leukemia NB4 cells","volume":"175","author":"Zhu","year":"2017","journal-title":"J. Inorg. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"224","DOI":"10.3945\/an.114.006874","article-title":"Zinc","volume":"6","author":"Huang","year":"2015","journal-title":"Adv. Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1097\/CEJ.0000000000000194","article-title":"Zinc as a possible preventive and therapeutic agent in pancreatic, prostate, and breast cancer","volume":"25","author":"Hoang","year":"2016","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"31","DOI":"10.4103\/abr.abr_7_15","article-title":"Determination Relation of the Zinc Serum Level in Acute Leukemia Adult Patients with Mucositis and Neutropenic Prevalence before and after Treatment in Isfahan\u2019 Seyed-Al-Shohada Hospital, 2012\u20132013","volume":"7","author":"Raisi","year":"2018","journal-title":"Adv. Biomed. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"146","DOI":"10.15430\/JCP.2019.24.3.146","article-title":"Effect of the Interaction Between Selenium and Zinc on DNA Repair in Association With Cancer Prevention","volume":"24","author":"Yildiz","year":"2019","journal-title":"J. Cancer Prev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1002\/jcb.22049","article-title":"The important role of the apoptotic effects of zinc in the development of cancers","volume":"106","author":"Franklin","year":"2009","journal-title":"J. Cell. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1093\/jn\/133.8.2543","article-title":"Zinc Deficiency Induces Oxidative DNA Damage and Increases P53 Expression in Human Lung Fibroblasts","volume":"133","author":"Ho","year":"2003","journal-title":"J. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1093\/jn\/138.4.667","article-title":"Zinc Deficiency Alters DNA Damage Response Genes in Normal Human Prostate Epithelial Cells","volume":"138","author":"Yan","year":"2008","journal-title":"J. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1093\/jn\/130.7.1688","article-title":"Expression of the p53 tumor suppressor gene is up-regulated by depletion of intracellular zinc in HepG2 cells","volume":"130","author":"Reaves","year":"2000","journal-title":"J. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3945\/ajcn.116.135327","article-title":"A moderate increase in dietary zinc reduces DNA strand breaks in leukocytes and alters plasma proteins without changing plasma zinc concentrations","volume":"105","author":"Zyba","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1152\/physrev.1993.73.1.79","article-title":"The biochemical basis of zinc physiology","volume":"73","author":"Vallee","year":"1993","journal-title":"Physiol. Rev."},{"key":"ref_24","first-page":"327","article-title":"Zinc differentially modulates DNA damage induced by anthracyclines in normal and cancer cells","volume":"34","author":"Wysokinski","year":"2012","journal-title":"Exp. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.cellbi.2009.02.004","article-title":"Zinc salts differentially modulate DNA damage in normal and cancer cells","volume":"33","author":"Czechowska","year":"2009","journal-title":"Cell Biol. Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.beha.2010.09.005","article-title":"Targeting DNA repair pathways in AML","volume":"23","year":"2010","journal-title":"Best Pr. Res. Clin. Haematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.2165\/11593060-000000000-00000","article-title":"Acute myeloid leukaemia: Optimal management and recent developments","volume":"71","author":"Villela","year":"2011","journal-title":"Drugs"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1038\/nprot.2007.77","article-title":"Cytokinesis-block micronucleus cytome assay","volume":"2","author":"Fenech","year":"2007","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2567\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:27:48Z","timestamp":1760135268000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2567"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,25]]},"references-count":28,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ijms23052567"],"URL":"https:\/\/doi.org\/10.3390\/ijms23052567","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,25]]}}}