Journal article
A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole
PLoS biology, Vol.12(3), pp.e1001815-e1001815
03/2014
DOI: 10.1371/journal.pbio.1001815
PMCID: PMC3958355
PMID: 24642609
Abstract
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.
Details
- Title: Subtitle
- A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole
- Creators
- Benjamin D Harrison - Department of Genetics, Cell, and Developmental Biology, University of Minnesota-Twin Cities, Minneapolis, Minnesota, United States of AmericaJordan Hashemi - Department of Electrical and Computer Engineering, Duke University, Durham, North Carolina, United States of AmericaMaayan Bibi - Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, IsraelRebecca Pulver - Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, IsraelDanny Bavli - Alexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem, IsraelYaakov Nahmias - Alexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem, IsraelMelanie Wellington - Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, United States of AmericaGuillermo Sapiro - Department of Electrical and Computer Engineering, Duke University, Durham, North Carolina, United States of AmericaJudith Berman - Department of Genetics, Cell, and Developmental Biology, University of Minnesota-Twin Cities, Minneapolis, Minnesota, United States of America; Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel
- Resource Type
- Journal article
- Publication Details
- PLoS biology, Vol.12(3), pp.e1001815-e1001815
- DOI
- 10.1371/journal.pbio.1001815
- PMID
- 24642609
- PMCID
- PMC3958355
- NLM abbreviation
- PLoS Biol
- ISSN
- 1544-9173
- eISSN
- 1545-7885
- Grant note
- T32 DE007288 / NIDCR NIH HHS T32DE007288 / NIDCR NIH HHS 340087 / European Research Council R01AI0624273 / NIAID NIH HHS
- Language
- English
- Date published
- 03/2014
- Academic Unit
- Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9984093348702771
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