A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole.
Candida albicans, the most prevalent human fungal pathogen, is generally diploid. However, 50% of isolates that are resistant to fluconazole (FLC), the most widely used antifungal, are aneuploid and some aneuploidies can confer FLC resistance. To ask if FLC exposure causes or only selects for aneupl...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-03-01
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| Series: | PLoS Biology |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24642609/pdf/?tool=EBI |
| _version_ | 1818939506352455680 |
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| author | Benjamin D Harrison Jordan Hashemi Maayan Bibi Rebecca Pulver Danny Bavli Yaakov Nahmias Melanie Wellington Guillermo Sapiro Judith Berman |
| author_facet | Benjamin D Harrison Jordan Hashemi Maayan Bibi Rebecca Pulver Danny Bavli Yaakov Nahmias Melanie Wellington Guillermo Sapiro Judith Berman |
| author_sort | Benjamin D Harrison |
| collection | DOAJ |
| description | Candida albicans, the most prevalent human fungal pathogen, is generally diploid. However, 50% of isolates that are resistant to fluconazole (FLC), the most widely used antifungal, are aneuploid and some aneuploidies can confer FLC resistance. To ask if FLC exposure causes or only selects for aneuploidy, we analyzed diploid strains during exposure to FLC using flow cytometry and epifluorescence microscopy. FLC exposure caused a consistent deviation from normal cell cycle regulation: nuclear and spindle cycles initiated prior to bud emergence, leading to "trimeras," three connected cells composed of a mother, daughter, and granddaughter bud. Initially binucleate, trimeras underwent coordinated nuclear division yielding four daughter nuclei, two of which underwent mitotic collapse to form a tetraploid cell with extra spindle components. In subsequent cell cycles, the abnormal number of spindles resulted in unequal DNA segregation and viable aneuploid progeny. The process of aneuploid formation in C. albicans is highly reminiscent of early stages in human tumorigenesis in that aneuploidy arises through a tetraploid intermediate and subsequent unequal DNA segregation driven by multiple spindles coupled with a subsequent selective advantage conferred by at least some aneuploidies during growth under stress. Finally, trimera formation was detected in response to other azole antifungals, in related Candida species, and in an in vivo model for Candida infection, suggesting that aneuploids arise due to azole treatment of several pathogenic yeasts and that this can occur during the infection process. |
| first_indexed | 2024-12-20T06:24:50Z |
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| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-20T06:24:50Z |
| publishDate | 2014-03-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Biology |
| spelling | doaj.art-2a1ac39e77b147f2b6b2b890f5c3243d2022-12-21T19:50:19ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852014-03-01123e100181510.1371/journal.pbio.1001815A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole.Benjamin D HarrisonJordan HashemiMaayan BibiRebecca PulverDanny BavliYaakov NahmiasMelanie WellingtonGuillermo SapiroJudith BermanCandida albicans, the most prevalent human fungal pathogen, is generally diploid. However, 50% of isolates that are resistant to fluconazole (FLC), the most widely used antifungal, are aneuploid and some aneuploidies can confer FLC resistance. To ask if FLC exposure causes or only selects for aneuploidy, we analyzed diploid strains during exposure to FLC using flow cytometry and epifluorescence microscopy. FLC exposure caused a consistent deviation from normal cell cycle regulation: nuclear and spindle cycles initiated prior to bud emergence, leading to "trimeras," three connected cells composed of a mother, daughter, and granddaughter bud. Initially binucleate, trimeras underwent coordinated nuclear division yielding four daughter nuclei, two of which underwent mitotic collapse to form a tetraploid cell with extra spindle components. In subsequent cell cycles, the abnormal number of spindles resulted in unequal DNA segregation and viable aneuploid progeny. The process of aneuploid formation in C. albicans is highly reminiscent of early stages in human tumorigenesis in that aneuploidy arises through a tetraploid intermediate and subsequent unequal DNA segregation driven by multiple spindles coupled with a subsequent selective advantage conferred by at least some aneuploidies during growth under stress. Finally, trimera formation was detected in response to other azole antifungals, in related Candida species, and in an in vivo model for Candida infection, suggesting that aneuploids arise due to azole treatment of several pathogenic yeasts and that this can occur during the infection process.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24642609/pdf/?tool=EBI |
| spellingShingle | Benjamin D Harrison Jordan Hashemi Maayan Bibi Rebecca Pulver Danny Bavli Yaakov Nahmias Melanie Wellington Guillermo Sapiro Judith Berman A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole. PLoS Biology |
| title | A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole. |
| title_full | A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole. |
| title_fullStr | A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole. |
| title_full_unstemmed | A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole. |
| title_short | A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole. |
| title_sort | tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24642609/pdf/?tool=EBI |
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