{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T11:53:54Z","timestamp":1793966034121,"version":"4.8.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Development Plan of Jining","award":["2023YXNS187"],"award-info":[{"award-number":["2023YXNS187"]}]},{"name":"Medical and Health Science and Technology Development Project of Shandong, China","award":["202411000427"],"award-info":[{"award-number":["202411000427"]}]},{"name":"Shandong medical staff science and technology innovation plan project","award":["SDYWZGKCJHLH2023079"],"award-info":[{"award-number":["SDYWZGKCJHLH2023079"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Superoxide dismutase (SOD) is a major antioxidant enzyme that protects cells against reactive oxygen species (ROS)-mediated oxidative stress. The identification of a fungal-specific copper-only SOD family in Candida albicans (C. albicans) has revealed a previously unrecognized component of fungal oxidative stress defence, yet the role of SOD6 remains unclear. Here, we generated a sod6\u0394\/\u0394 mutant in C. albicans using a transient CRISPR\/Cas9 approach and examined the contribution of SOD6 to virulence, ROS homeostasis, oxidative stress resistance, and genome maintenance. Compared with the wild-type (WT) strain, the sod6\u0394\/\u0394 mutant showed attenuated virulence in both the Galleria mellonella (G. mellonell) infection model and a murine systemic candidiasis model. This virulence defect occurred without detectable alterations in hyphal formation or other major pathogenicity-associated traits. Instead, the mutant accumulated higher intracellular and extracellular ROS levels and displayed increased sensitivity to hydrogen peroxide, zeocin, and camptothecin (CPT), consistent with impaired oxidative stress adaptation and genome maintenance. Transcriptomic analysis further revealed downregulation of genes involved in DNA replication and repair, with dpb4, which encodes a subunit of DNA polymerase epsilon required for DNA replication and genome stability, showing the greatest reduction. Together, these findings identify SOD6 as an important determinant of oxidative stress adaptation, genome maintenance, and pathogenic fitness in C. albicans.<\/jats:p>","DOI":"10.1093\/mmy\/myag063","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T11:46:28Z","timestamp":1781783188000},"source":"Crossref","is-referenced-by-count":1,"title":["Copper-only Superoxide dismutase 6 contributes to reactive oxygen species regulation, genotoxic stress tolerance, and virulence in\n                    <i>Candida albicans<\/i>"],"prefix":"10.1093","volume":"64","author":[{"given":"Zhiwei","family":"Liu","sequence":"first","affiliation":[{"name":"The Laboratory of Central, Jining No.1 People Hospital , Jining ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengxue","family":"Li","sequence":"additional","affiliation":[{"name":"The Laboratory of Central, Jining No.1 People Hospital , Jining ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiule","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Science and Engineering, Jining University , Jining ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biao","family":"Chen","sequence":"additional","affiliation":[{"name":"The Laboratory of Central, Jining No.1 People Hospital , Jining ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"issue":"1","key":"2026070103564409200_bib1","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/s41572-024-00503-3","article-title":"Invasive candidiasis","volume":"10","author":"Lass-Fl\u00f6rl","year":"2024","journal-title":"Nat Rev Dis Primers"},{"issue":"11","key":"2026070103564409200_bib2","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1038\/s41579-024-01062-w","article-title":"The pathobiology of human fungal infections","volume":"22","author":"Brown","year":"2024","journal-title":"Nat Rev Micro"},{"issue":"4","key":"2026070103564409200_bib3","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/s41579-023-00861-x","article-title":"The WHO fungal priority pathogens list as a game-changer","volume":"21","author":"Fisher","year":"2023","journal-title":"Nat Rev Micro."},{"issue":"7","key":"2026070103564409200_bib4","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/s41577-022-00826-w","article-title":"Immune responses to human fungal pathogens and therapeutic prospects","volume":"23","author":"Lionakis","year":"2023","journal-title":"Nat Rev Immunol."},{"issue":"6","key":"2026070103564409200_bib5","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1093\/cid\/ciac004","article-title":"Attributable mortality of Candida bloodstream infections in the modern era: a propensity score analysis","volume":"75","author":"Mazi","year":"2022","journal-title":"Clin Infect Dis"},{"key":"2026070103564409200_bib6","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1038\/s41579-024-01105-2","article-title":"Bloodstream infections: mechanisms of pathogenesis and opportunities for intervention","volume":"23","author":"Holmes","year":"2025","journal-title":"Nat Rev Micro."},{"issue":"3","key":"2026070103564409200_bib7","doi-asserted-by":"publisher","first-page":"501","DOI":"10.3390\/antiox11030501","article-title":"Superoxide radicals in the execution of cell death","volume":"11","author":"Fujii","year":"2022","journal-title":"Antioxidants (Basel)"},{"issue":"1","key":"2026070103564409200_bib8","doi-asserted-by":"publisher","first-page":"mfag007","DOI":"10.1093\/mtomcs\/mfag007","article-title":"From hemocuprein to CSRP: the many faces of Cu\/Zn superoxide dismutase","volume":"18","author":"Peterson","year":"2026","journal-title":"Metallomics"},{"issue":"10","key":"2026070103564409200_bib9","doi-asserted-by":"publisher","first-page":"6010","DOI":"10.1021\/acs.jafc.4c09697","article-title":"Novel thermostable manganese superoxide dismutase from Alicyclobacillus sp. with high specific activity and antioxidant properties","volume":"73","author":"Sun","year":"2025","journal-title":"J Agric Food Chem"},{"issue":"13","key":"2026070103564409200_bib10","doi-asserted-by":"publisher","first-page":"4636","DOI":"10.1074\/jbc.TM117.000182","article-title":"Eukaryotic copper-only superoxide dismutases (SODs): a new class of SOD enzymes and SOD-like protein domains","volume":"293","author":"Robinett","year":"2018","journal-title":"J Biol Chem"},{"issue":"16","key":"2026070103564409200_bib11","doi-asserted-by":"publisher","first-page":"5866","DOI":"10.1073\/pnas.1400137111","article-title":"Candida albicans SOD5 represents the prototype of an unprecedented class of Cu-only superoxide dismutases required for pathogen defense","volume":"111","author":"Gleason","year":"2014","journal-title":"Proc Nat Acad Sci USA"},{"issue":"1","key":"2026070103564409200_bib12","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s12866-024-03213-8","article-title":"Transcriptomic meta-analysis to identify potential antifungal targets in Candida albicans","volume":"24","author":"Hefny","year":"2024","journal-title":"BMC Microbiol"},{"issue":"1","key":"2026070103564409200_bib13","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1111\/j.1365-2958.2008.06528.x","article-title":"Candida albicans cell surface superoxide dismutases degrade host-derived reactive oxygen species to escape innate immune surveillance","volume":"71","author":"Frohner","year":"2009","journal-title":"Mol Microbiol"},{"issue":"2","key":"2026070103564409200_bib14","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1091\/mbc.e03-03-0179","article-title":"Superoxide dismutases in Candida albicans: transcriptional regulation and functional characterization of the hyphal-induced SOD5 gene","volume":"15","author":"Martchenko","year":"2004","journal-title":"Mol Biol Cell"},{"issue":"2","key":"2026070103564409200_bib15","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1111\/j.1365-2958.2005.04557.x","article-title":"Granulocytes govern the transcriptional response, morphology and proliferation of Candida albicans in human blood","volume":"56","author":"Fradin","year":"2005","journal-title":"Mol Microbiol"},{"issue":"1","key":"2026070103564409200_bib16","doi-asserted-by":"publisher","first-page":"22374","DOI":"10.1038\/s41598-024-71959-2","article-title":"Study on the mechanism of ROS-induced oxidative stress injury and the broad-spectrum antimicrobial performance of nickel ion-doped V6O13 powder","volume":"14","author":"Liu","year":"2024","journal-title":"Sci Rep"},{"issue":"1","key":"2026070103564409200_bib17","doi-asserted-by":"publisher","first-page":"2433201","DOI":"10.1080\/21505594.2024.2433201","article-title":"DNA damage repair factor Rad18 controls pathogenicity partially via transcriptional suppression of genes HWP1 and ECE1 in Candida albicans","volume":"15","author":"Chen","year":"2024","journal-title":"pathogenicity"},{"issue":"1","key":"2026070103564409200_bib18","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1186\/s12866-023-03069-4","article-title":"The regulatory subunits of CK2 complex mediate DNA damage response and pathogenicity in Candida glabrata","volume":"23","author":"Ni","year":"2023","journal-title":"BMC Microbiol"},{"issue":"1","key":"2026070103564409200_bib19","doi-asserted-by":"publisher","first-page":"e00062","DOI":"10.1128\/mSphere.00062-20","article-title":"Nucleotide excision repair protein Rad23 regulates cell pathogenicity independent of Rad4 in Candida albicans","volume":"5","author":"Feng","year":"2020","journal-title":"mSphere"},{"issue":"14","key":"2026070103564409200_bib20","doi-asserted-by":"publisher","first-page":"7555","DOI":"10.3390\/ijms23147555","article-title":"Transcriptional Profiling of the Candida albicans response to the DNA damage agent methyl methanesulfonate","volume":"23","author":"Feng","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2026070103564409200_bib21","doi-asserted-by":"publisher","first-page":"106507","DOI":"10.1016\/j.micpath.2023.106507","article-title":"Systematic identification and characterization of five transcription factors mediating the oxidative stress response in Candida albicans","volume":"187","author":"Cui","year":"2024","journal-title":"Microb Pathog"},{"issue":"10","key":"2026070103564409200_bib22","doi-asserted-by":"publisher","first-page":"e0122724","DOI":"10.1128\/mbio.01227-24","article-title":"Critical roles of Dpb3-Dpb4 sub-complex of DNA polymerase epsilon in DNA replication, genome stability, and pathogenesis of Candida albicans","volume":"15","author":"Utkalaja","year":"2024","journal-title":"mBio"},{"issue":"1","key":"2026070103564409200_bib23","doi-asserted-by":"publisher","first-page":"3781","DOI":"10.1038\/s41467-022-31237-z","article-title":"Trans-cellular tunnels induced by the fungal pathogen Candida albicans facilitate invasion through successive epithelial cells without host damage","volume":"13","author":"Lachat","year":"2022","journal-title":"Nat Commun"},{"issue":"5","key":"2026070103564409200_bib24","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1016\/s0092-8674(00)80358-x","article-title":"Nonfilamentous C. albicans mutants are avirulent","volume":"90","author":"Lo","year":"1997","journal-title":"Cell"},{"issue":"9","key":"2026070103564409200_bib25","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1111\/j.1462-5822.2012.01813.x","article-title":"Host carbon sources modulate cell wall architecture, drug resistance and pathogenicity in a fungal pathogen","volume":"14","author":"Ene","year":"2012","journal-title":"Cell Microbiol"},{"issue":"4","key":"2026070103564409200_bib26","doi-asserted-by":"publisher","first-page":"e0259324","DOI":"10.1128\/spectrum.02593-24","article-title":"Profilin Pfy1 is critical for cell wall integrity and pathogenicity in Candida albicans","volume":"13","author":"Sun","year":"2025","journal-title":"Microbiol Spectr"},{"issue":"1","key":"2026070103564409200_bib27","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/s10522-020-09904-9","article-title":"Astaxanthin protects oxidative stress mediated DNA damage and enhances longevity in Saccharomyces cerevisiae","volume":"22","author":"Sudharshan","year":"2021","journal-title":"Biogerontology"},{"issue":"1","key":"2026070103564409200_bib28","doi-asserted-by":"publisher","first-page":"3119","DOI":"10.1038\/s41598-024-53264-0","article-title":"Zeocin-induced DNA damage response in barley and its dependence on ATR","volume":"14","author":"Vladeji\u0107","year":"2024","journal-title":"Sci Rep"},{"key":"2026070103564409200_bib29","doi-asserted-by":"publisher","first-page":"109875","DOI":"10.1016\/j.biopha.2020.109875","article-title":"The role of single strand break repair pathways in cellular responses to camptothecin induced DNA damage","volume":"125","author":"Mei","year":"2020","journal-title":"Biomed Pharmacother"},{"issue":"6","key":"2026070103564409200_bib30","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1083\/jcb.201708007","article-title":"Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling","volume":"217","author":"Wang","year":"2018","journal-title":"J Cell Biol"},{"issue":"1","key":"2026070103564409200_bib31","doi-asserted-by":"publisher","first-page":"e1005295","DOI":"10.1371\/journal.ppat.1005295","article-title":"SOD enzymes and microbial pathogens: surviving the oxidative storm of infection","volume":"12","author":"Broxton","year":"2016","journal-title":"PLoS Pathog"},{"issue":"40","key":"2026070103564409200_bib32","doi-asserted-by":"publisher","first-page":"20911","DOI":"10.1074\/jbc.M116.748251","article-title":"The Phylogeny and Active Site Design of Eukaryotic Copper-only Superoxide Dismutases","volume":"291","author":"Peterson","year":"2016","journal-title":"J Biol Chem"},{"issue":"2","key":"2026070103564409200_bib33","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1074\/jbc.RA119.011084","article-title":"Copper-only superoxide dismutase enzymes and iron starvation stress in Candida fungal pathogens","volume":"295","author":"Schatzman","year":"2020","journal-title":"J Biol Chem"},{"issue":"3","key":"2026070103564409200_bib34","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1080\/09553002.2021.2003464","article-title":"Chemistry of ROS-mediated oxidation to the guanine base in DNA and its biological consequences","volume":"98","author":"Fleming","year":"2022","journal-title":"Int J Radiat Biol"},{"key":"2026070103564409200_bib35","doi-asserted-by":"publisher","first-page":"213","DOI":"10.3389\/fmicb.2020.00213","article-title":"SPT20 regulates the Hog1-MAPK pathway and is involved in Candida albicans response to hyperosmotic stress","volume":"11","author":"Wang","year":"2020","journal-title":"Front Microbiol"},{"issue":"5","key":"2026070103564409200_bib36","doi-asserted-by":"publisher","first-page":"104624","DOI":"10.1016\/j.jbc.2023.104624","article-title":"H2O2 transit through the mitochondrial intermembrane space promotes tumor cell growth in vitro and in vivo","volume":"299","author":"Sabharwal","year":"2023","journal-title":"J Biol Chem"},{"issue":"1","key":"2026070103564409200_bib37","doi-asserted-by":"publisher","first-page":"4750","DOI":"10.1038\/s41467-021-25090-9","article-title":"Dpb4 promotes resection of DNA double-strand breaks and checkpoint activation by acting in two different protein complexes","volume":"12","author":"Casari","year":"2021","journal-title":"Nat Commun"},{"issue":"12","key":"2026070103564409200_bib38","doi-asserted-by":"publisher","first-page":"5309","DOI":"10.1111\/1462-2920.15236","article-title":"A Cu-only superoxide dismutase from stripe rust fungi functions as a pathogenicity factor deployed for counter defense against host-derived oxidative stress","volume":"22","author":"Zheng","year":"2020","journal-title":"Environ Microbiol"},{"issue":"1","key":"2026070103564409200_bib39","doi-asserted-by":"publisher","first-page":"2156","DOI":"10.1038\/s41467-025-57346-z","article-title":"Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans","volume":"16","author":"Puumala","year":"2025","journal-title":"Nat Commun"},{"issue":"3","key":"2026070103564409200_bib40","doi-asserted-by":"publisher","first-page":"e1500248","DOI":"10.1126\/sciadv.1500248","article-title":"Candida albicans CRISPR system permits genetic engineering of essential genes and gene families","volume":"1","author":"Vyas","year":"2015","journal-title":"Sci Adv"},{"issue":"6","key":"2026070103564409200_bib41","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1016\/j.micinf.2010.03.001","article-title":"Role of filamentation in Galleria mellonella killing by Candida albicans","volume":"12","author":"Fuchs","year":"2010","journal-title":"Microbes Infect"},{"issue":"16","key":"2026070103564409200_bib42","doi-asserted-by":"publisher","first-page":"3617","DOI":"10.1111\/bph.15193","article-title":"The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research","volume":"177","author":"Percie\u00a0du\u00a0Sert","year":"2020","journal-title":"Br J Pharmacol"},{"issue":"1","key":"2026070103564409200_bib43","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1080\/21501203.2024.2354876","article-title":"Mitochondrial phosphate carrier plays an important role in virulence of Candida albicans","volume":"16","author":"Hu","year":"2024","journal-title":"Mycology"},{"issue":"5","key":"2026070103564409200_bib44","doi-asserted-by":"publisher","first-page":"e0070721","DOI":"10.1128\/mSphere.00707-21","article-title":"Candida albicans ENT2 contributes to efficient endocytosis, cell wall integrity, filamentation, and pathogenicity","volume":"6","author":"Rollenhagen","year":"2021","journal-title":"mSphere"},{"issue":"7","key":"2026070103564409200_bib45","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1042\/BCJ20160889","article-title":"Characterization of Pph3-mediated dephosphorylation of Rad53 during methyl methanesulfonate-induced DNA damage repair in Candida albicans","volume":"474","author":"Yao","year":"2017","journal-title":"Biochem J"},{"issue":"12","key":"2026070103564409200_bib46","doi-asserted-by":"publisher","first-page":"2567","DOI":"10.1534\/g3.115.021840","article-title":"The role of Mms22p in DNA damage response in Candida albicans","volume":"5","author":"Yan","year":"2015","journal-title":"G3 (Bethesda)"},{"issue":"4","key":"2026070103564409200_bib47","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods (San Diego, Calif.)"}],"container-title":["Medical Mycology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/mmy\/advance-article-pdf\/doi\/10.1093\/mmy\/myag063\/68559946\/myag063.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/mmy\/article-pdf\/64\/7\/myag063\/68559946\/myag063.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/mmy\/article-pdf\/64\/7\/myag063\/68559946\/myag063.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T14:56:40Z","timestamp":1782917800000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/mmy\/article\/doi\/10.1093\/mmy\/myag063\/8711773"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,19]]},"references-count":47,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7,1]]}},"URL":"https:\/\/doi.org\/10.1093\/mmy\/myag063","relation":{},"ISSN":["1369-3786","1460-2709"],"issn-type":[{"value":"1369-3786","type":"print"},{"value":"1460-2709","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,7]]},"published":{"date-parts":[[2026,6,19]]},"article-number":"myag063"}}