{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:04:02Z","timestamp":1791237842329,"version":"4.1.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T00:00:00Z","timestamp":1615161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM084176"],"award-info":[{"award-number":["GM084176"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"United States Department of Education GAANN","award":["P200A150114"],"award-info":[{"award-number":["P200A150114"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The ability of pathogens to maintain homeostatic levels of essential biometals is known to be important for survival and virulence in a host, which itself regulates metal availability as part of its response to infection. Given this importance of metal homeostasis, we sought to address how the availability of copper in particular impacts the response of the opportunistic fungal pathogen Candida albicans to treatment with the antifungal drug fluconazole. The present study reports whole transcriptome analysis via time-course RNA-seq of C. albicans cells exposed to fluconazole with and without 10\u2009\u00b5M supplemental CuSO4 added to the growth medium. The results show widespread impacts of small changes in Cu availability on the transcriptional response of C. albicans to fluconazole. Of the 2359 genes that were differentially expressed under conditions of cotreatment, 50% were found to be driven uniquely by exposure to both Cu and fluconazole. The breadth of metabolic processes that were affected by cotreatment illuminates a fundamental intersectionality between Cu metabolism and fungal response to drug stress. More generally, these results show that seemingly minor fluctuations in Cu availability are sufficient to shift cells\u2019 transcriptional response to drug stress. Ultimately, the findings may inform the development of new strategies that capitalize on drug-induced vulnerabilities in metal homeostasis pathways.<\/jats:p>","DOI":"10.1093\/g3journal\/jkab065","type":"journal-article","created":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T06:43:11Z","timestamp":1615444991000},"source":"Crossref","is-referenced-by-count":14,"title":["Copper Availability Influences the Transcriptomic Response of <i>Candida albicans<\/i> to Fluconazole Stress"],"prefix":"10.1093","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6008-8599","authenticated-orcid":false,"given":"Elizabeth W","family":"Hunsaker","sequence":"first","affiliation":[{"name":"Department of Chemistry, French Family Science Center, Duke University, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5662-3026","authenticated-orcid":false,"given":"Chen-Hsin Albert","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9015-0998","authenticated-orcid":false,"given":"Katherine J","family":"Franz","sequence":"additional","affiliation":[{"name":"Department of Chemistry, French Family Science Center, Duke University, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,8]]},"reference":[{"key":"2021041518252925400_jkab065-B1","doi-asserted-by":"crossref","first-page":"4628","DOI":"10.1074\/jbc.R117.000176","article-title":"Copper signaling in the brain and beyond","volume":"293","author":"Ackerman","year":"2018","journal-title":"J Biol Chem"},{"key":"2021041518252925400_jkab065-B2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat Genet"},{"key":"2021041518252925400_jkab065-B3","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.abb.2016.01.010","article-title":"Synthesis, delivery and regulation of eukaryotic heme and Fe\u2013S cluster cofactors","volume":"592","author":"Barupala","year":"2016","journal-title":"Arch Biochem Biophys"},{"key":"2021041518252925400_jkab065-B4","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s00775-016-1335-1","article-title":"The Yin and Yang of copper during infection","volume":"21","author":"Besold","year":"2016","journal-title":"J Biol Inorg Chem"},{"key":"2021041518252925400_jkab065-B5","doi-asserted-by":"crossref","first-page":"e01291","DOI":"10.1128\/mBio.01291-18","article-title":"Overexpression or deletion of ergosterol biosynthesis genes alters doubling time, response to stress agents, and drug susceptibility in Saccharomyces cerevisiae","volume":"9","author":"Bhattacharya","year":"2018","journal-title":"mBio"},{"key":"2021041518252925400_jkab065-B6","doi-asserted-by":"crossref","first-page":"e0168400","DOI":"10.1371\/journal.pone.0168400","article-title":"An adaptation to low copper in Candida albicans involving SOD enzymes and the alternative oxidase","volume":"11","author":"Broxton","year":"2016","journal-title":"PLoS ONE"},{"key":"2021041518252925400_jkab065-B7","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.chom.2011.07.005","article-title":"An iron homeostasis regulatory circuit with reciprocal roles in Candida albicans commensalism and pathogenesis","volume":"10","author":"Chen","year":"2011","journal-title":"Cell Host Microbe"},{"key":"2021041518252925400_jkab065-B8","doi-asserted-by":"crossref","first-page":"e1002777","DOI":"10.1371\/journal.ppat.1002777","article-title":"Candida albicans scavenges host zinc via Pra1 during endothelial invasion","volume":"8","author":"Citiulo","year":"2012","journal-title":"PLoS Pathog"},{"key":"2021041518252925400_jkab065-B9","doi-asserted-by":"crossref","first-page":"e1007013","DOI":"10.1371\/journal.ppat.1007013","article-title":"Biphasic zinc compartmentalisation in a human fungal pathogen","volume":"14","author":"Crawford","year":"2018","journal-title":"PLoS Pathog"},{"key":"2021041518252925400_jkab065-B10","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1039\/C9MT00294D","article-title":"Changes in mammalian copper homeostasis during microbial infection","volume":"12","author":"Culbertson","year":"2020","journal-title":"Metallomics"},{"key":"2021041518252925400_jkab065-B11","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3389\/fcimb.2018.00185","article-title":"Iron at the centre of Candida albicans interactions","volume":"8","author":"Fourie","year":"2018","journal-title":"Front Cell Infect Microbiol"},{"key":"2021041518252925400_jkab065-B12","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1039\/C0MB00166J","article-title":"Suppression of statin effectiveness by copper and zinc in yeast and human cells","volume":"7","author":"Fowler","year":"2011","journal-title":"Mol Biosyst"},{"key":"2021041518252925400_jkab065-B13","doi-asserted-by":"crossref","DOI":"10.1093\/femsre\/fux050","article-title":"Metals in fungal virulence","volume":"42","author":"Gerwien","year":"2018","journal-title":"FEMS Microbiol Rev"},{"key":"2021041518252925400_jkab065-B14","doi-asserted-by":"crossref","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 Natl Acad Sci USA"},{"key":"2021041518252925400_jkab065-B15","doi-asserted-by":"crossref","first-page":"6728","DOI":"10.1074\/jbc.M117.778308","article-title":"Structural analyses of Candida albicans sterol 14\u03b1-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis","volume":"292","author":"Hargrove","year":"2017","journal-title":"J Biol Chem"},{"key":"2021041518252925400_jkab065-B16","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1002\/jms.280","article-title":"Mechanism of azole antifungal activity as determined by liquid chromatographic\/mass spectrometric monitoring of ergosterol biosynthesis","volume":"37","author":"Heimark","year":"2002","journal-title":"J Mass Spectrom"},{"key":"2021041518252925400_jkab065-B17","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1021\/cr9500390","article-title":"Structural and functional aspects of metal sites in biology","volume":"96","author":"Holm","year":"1996","journal-title":"Chem Rev"},{"key":"2021041518252925400_jkab065-B18","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1038\/nchembio.1662","article-title":"Subcellular metal imaging identifies dynamic sites of Cu accumulation in Chlamydomonas","volume":"10","author":"Hong-Hermesdorf","year":"2014","journal-title":"Nat Chem Biol"},{"key":"2021041518252925400_jkab065-B19","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1039\/C9MT00228F","article-title":"Candida albicans reprioritizes metal handling during fluconazole stress","volume":"11","author":"Hunsaker","year":"2019","journal-title":"Metallomics"},{"key":"2021041518252925400_jkab065-B20","doi-asserted-by":"crossref","first-page":"9654","DOI":"10.1039\/C9DT00642G","article-title":"Copper potentiates azole antifungal activity in a way that does not involve complex formation","volume":"48","author":"Hunsaker","year":"2019","journal-title":"Dalton Trans"},{"key":"2021041518252925400_jkab065-B21","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"2021041518252925400_jkab065-B22","doi-asserted-by":"crossref","first-page":"D277","DOI":"10.1093\/nar\/gkh063","article-title":"The KEGG resource for deciphering the genome","volume":"32","author":"Kanehisa","year":"2004","journal-title":"Nucleic Acids Res"},{"key":"2021041518252925400_jkab065-B23","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1006\/bbrc.1995.1272","article-title":"Mode of action and resistance to azole antifungals associated with the formation of 14\u03b1-Methylergosta-8,24(28)-dien-3\u03b2,6\u03b1-diol","volume":"207","author":"Kelly","year":"1995","journal-title":"Biochem Biophys Res Commun"},{"key":"2021041518252925400_jkab065-B24","doi-asserted-by":"crossref","first-page":"935","DOI":"10.3389\/fmicb.2020.00935","article-title":"Transcriptome analysis uncovers a link between copper metabolism, and both fungal fitness and antifungal sensitivity in the opportunistic yeast Candida albicans","volume":"11","author":"Khemiri","year":"2020","journal-title":"Front Microbiol"},{"key":"2021041518252925400_jkab065-B25","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3390\/ijms20010175","article-title":"The role of copper homeostasis at the host-pathogen axis: from bacteria to fungi","volume":"20","author":"Li","year":"2019","journal-title":"Int J Mol Sci"},{"key":"2021041518252925400_jkab065-B26","doi-asserted-by":"crossref","first-page":"E5336","DOI":"10.1073\/pnas.1513447112","article-title":"Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase","volume":"112","author":"Li","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021041518252925400_jkab065-B27","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1006\/jmbi.1999.2815","article-title":"Mutational analysis of Saccharomyces cerevisiae Smf1p, a member of the Nramp family of metal transporters","volume":"289","author":"Liu","year":"1999","journal-title":"J Mol Biol"},{"key":"2021041518252925400_jkab065-B28","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/1472-6750-13-68","article-title":"The effects of statins on the mevalonic acid pathway in recombinant yeast strains expressing human HMG-CoA reductase","volume":"13","author":"Maciejak","year":"2013","journal-title":"BMC Biotechnol"},{"key":"2021041518252925400_jkab065-B29","doi-asserted-by":"crossref","first-page":"e0158683","DOI":"10.1371\/journal.pone.0158683","article-title":"Host-stemic Candida albicans infections","volume":"11","author":"Mackie","year":"2016","journal-title":"PLoS ONE"},{"key":"2021041518252925400_jkab065-B30","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1099\/mic.0.27004-0","article-title":"The CaCTR1 gene is required for high-affinity iron uptake and is transcriptionally controlled by a copper-sensing transactivator encoded by CaMAC1","volume":"150","author":"Marvin","year":"2004","journal-title":"Microbiology"},{"key":"2021041518252925400_jkab065-B31","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1099\/mic.0.26172-0","article-title":"The Candida albicans CTR1 gene encodes a functional copper transporter","volume":"149","author":"Marvin","year":"2003","journal-title":"Microbiology"},{"key":"2021041518252925400_jkab065-B32","doi-asserted-by":"crossref","first-page":"555","DOI":"10.2174\/1389557516666160118112103","article-title":"The mechanistic targets of antifungal agents: an overview","volume":"16","author":"Mazu","year":"2016","journal-title":"Mini Rev Med Chem"},{"key":"2021041518252925400_jkab065-B33","doi-asserted-by":"crossref","first-page":"140206","DOI":"10.1016\/j.bbapap.2019.02.008","article-title":"Fungal Lanosterol 14\u03b1-demethylase: a target for next-generation antifungal design","volume":"1868","author":"Monk","year":"2020","journal-title":"Biochim Biophys Acta Proteins Proteom"},{"key":"2021041518252925400_jkab065-B34","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.mib.2013.09.006","article-title":"Candida albicans specializations for iron homeostasis: from commensalism to virulence","volume":"16","author":"Noble","year":"2013","journal-title":"Curr Opin Microbiol"},{"key":"2021041518252925400_jkab065-B35","doi-asserted-by":"crossref","first-page":"7893","DOI":"10.1128\/MCB.20.21.7893-7902.2000","article-title":"Saccharomyces cerevisiae expresses three functionally distinct homologues of the Nramp family of metal transporters","volume":"20","author":"Portnoy","year":"2000","journal-title":"Mol Cell Biol"},{"key":"2021041518252925400_jkab065-B36","doi-asserted-by":"crossref","first-page":"4722","DOI":"10.1021\/cr900031u","article-title":"Manganese homeostasis in Saccharomyces cerevisiae","volume":"109","author":"Reddi","year":"2009","journal-title":"Chem Rev"},{"key":"2021041518252925400_jkab065-B37","doi-asserted-by":"crossref","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":"2019","journal-title":"J Biol Chem"},{"key":"2021041518252925400_jkab065-B38","doi-asserted-by":"crossref","first-page":"D592","DOI":"10.1093\/nar\/gkw924","article-title":"The Candida genome database (CGD): incorporation of Assembly 22, systematic identifiers and visualization of high throughput sequencing data","volume":"45","author":"Skrzypek","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2021041518252925400_jkab065-B39","first-page":"D330","article-title":"The gene ontology resource: 20 years and still going strong","volume":"47","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"2021041518252925400_jkab065-B40","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/0006-291X(89)91792-0","article-title":"Defective sterol C5-6 desaturation and azole resistance: a new hypothesis for the mode of action of azole antifungals","volume":"164","author":"Watson","year":"1989","journal-title":"Biochem Biophys Res Commun"},{"key":"2021041518252925400_jkab065-B41","doi-asserted-by":"crossref","first-page":"3520","DOI":"10.1073\/pnas.97.7.3520","article-title":"The high copper tolerance of Candida albicans is mediated by a P-type ATPase","volume":"97","author":"Weissman","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021041518252925400_jkab065-B42","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.bbamcr.2013.12.009","article-title":"Cellular iron homeostasis mediated by the Mrs4\u2013Ccc1\u2013Smf3 pathway is essential for mitochondrial function, morphogenesis and virulence in Candida albicans","volume":"1843","author":"Xu","year":"2014","journal-title":"Biochim Biophys Acta"}],"container-title":["G3 Genes|Genomes|Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/g3journal\/advance-article-pdf\/doi\/10.1093\/g3journal\/jkab065\/36950061\/jkab065.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/g3journal\/article-pdf\/11\/4\/jkab065\/37083103\/jkab065.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/g3journal\/article-pdf\/11\/4\/jkab065\/37083103\/jkab065.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,17]],"date-time":"2021-04-17T06:19:08Z","timestamp":1618640348000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/g3journal\/article\/doi\/10.1093\/g3journal\/jkab065\/6162163"}},"subtitle":[],"editor":[{"given":"Brenda","family":"Andrews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,3,8]]},"references-count":42,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,4,15]]}},"URL":"https:\/\/doi.org\/10.1093\/g3journal\/jkab065","relation":{},"ISSN":["2160-1836"],"issn-type":[{"value":"2160-1836","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,4,1]]},"published":{"date-parts":[[2021,3,8]]},"article-number":"jkab065"}}