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...

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Autores principales:	Benjamin D Harrison, Jordan Hashemi, Maayan Bibi, Rebecca Pulver, Danny Bavli, Yaakov Nahmias, Melanie Wellington, Guillermo Sapiro, Judith Berman
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/2a1ac39e77b147f2b6b2b890f5c3243d
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spelling	oai:doaj.org-article:2a1ac39e77b147f2b6b2b890f5c3243d2021-11-18T05:37:32ZA tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole.1544-91731545-788510.1371/journal.pbio.1001815https://doaj.org/article/2a1ac39e77b147f2b6b2b890f5c3243d2014-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24642609/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Candida 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.Benjamin D HarrisonJordan HashemiMaayan BibiRebecca PulverDanny BavliYaakov NahmiasMelanie WellingtonGuillermo SapiroJudith BermanPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 12, Iss 3, p e1001815 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 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.
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.
format	article
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
title	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_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_sort	tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/2a1ac39e77b147f2b6b2b890f5c3243d
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A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole.

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