A natural histone H2A variant lacking the Bub1 phosphorylation site and regulated depletion of centromeric histone CENP-A foster evolvability in Candida albicans
Open accessAbstract
Eukaryotes have evolved elaborate mechanisms to ensure that chromosomes segregate with high fidelity during mitosis and meiosis, and yet specific aneuploidies can be adaptive during environmental stress. Here, we identify a chromatin-based system required for inducible aneuploidy in a human pathogen. Candida albicans utilizes chromosome missegregation to acquire tolerance to antifungal drugs and for nonmeiotic ploidy reduction after mating. We discovered that the ancestor of C. albicans and 2 related pathogens evolved a variant of histone 2A (H2A) that lacks the conserved phosphorylation site for kinetochore-associated Bub1 kinase, a key regulator of chromosome segregation. Using engineered strains, we show that the relative gene dosage of this variant versus canonical H2A controls the fidelity of chromosome segregation and the rate of acquisition of tolerance to antifungal drugs via aneuploidy. Furthermore, whole-genome chromatin precipitation analysis reveals that Centromere Protein A/ Centromeric Histone H3-like Protein (CENP-A/Cse4), a centromeric histone H3 variant that forms the platform of the eukaryotic kinetochore, is depleted from tetraploid-mating products relative to diploid parents and is virtually eliminated from cells exposed to aneuploidy-promoting cues. We conclude that genetically programmed and environmentally induced changes in chromatin can confer the capacity for enhanced evolvability via chromosome missegregation.
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About 50% of all fluconazole-resistant Candida albicans isolates contain at least one aneuploid chromosome, and chromosomal instability can increase the frequency of fluconazole-resistant cells.
“Additionally, ∼50% of all FLC-resistant C. albicans isolates contain at least one aneuploid chromosome (Selmecki et al. 2006) and chromosomal instability, in general, can increase the frequency of FLC-resistant cells (Brimacombe et al. 2019; Yang, Todd, et al. 2021).”
From Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in <i>Candida albicans</i> (2023) · cites this paper as Brimacombe et al. 2019
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- Authors
- Brimacombe, C. A., Burke, J. E., Parsa, J.-Y., Catania, S., O’Meara, T. R., Witchley, J. N., Burrack, L. S., Madhani, H. D., & Noble, S. M.
- Affiliations
- University of California, San Francisco (US)
- Gustavus Adolphus College (US)
- Corresponding author
- Noble, Suzanne M.
- ORCID
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2019-06-21
- Volume
- 17
- Issue
- 6
- Pages
- e3000331
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC6613695
- OpenAlex
- W2950912819
- Cited by
- 22
- References
- 51
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 1
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Update notices
- new_version (2019-07-08)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health (R01AI108992, T32AI060537, R01AI120464)
- American Cancer Society (Postdoctoral Fellowship)
- Chan-Zuckerberg Biohub (Senior Investigator)
- Burroughs Wellcome Fund (Investigator of the Pathogenesis of Infectious Diseases)
- Pew Charitable Trusts (Scholar in the Biomedical Sciences)
- National Institures of Health (RO1 GM071801)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- histone H2A variant, Bub1 kinase, Cse4, chromosome segregation, chromosome missegregation, aneuploidy, evolvability, Candida albicans, antifungal drug tolerance, kinetochore, centromere, tetraploidy, gene dosage, chromatin evolution
- MeSH terms
- Centromere Protein A, Aneuploidy, Candida albicans, Centromere, Chromatin, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, Histones, Meiosis, Mitosis, Phosphorylation, Protein Serine-Threonine Kinases, Kinetochores, Cell Cycle Proteins, Evolution, Molecular, Chromosome Segregation, Aneugens
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