A natural histone H2A variant lacking the Bub1 phosphorylation site and regulated depletion of centromeric histone CENP-A foster evolvability in Candida albicans.

Cedric A Brimacombe,Laura S Burrack,Jordan E Burke,Hiten D Madhani,Jahan-Yar Parsa,Suzanne M Noble,Teresa R O’Meara,Sandra Catania,Jessica N Witchley

doi:10.1371/journal.pbio.3000331

Cedric A Brimacombe, Laura S Burrack + Show 7 more

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https://doi.org/10.1371/journal.pbio.3000331

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Abstract

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.

Highlights

Aneuploidy is increasingly recognized as an important form of natural variation in eukaryotes
A search for homologs of Bub1, Shugoshin 1 (Sgo1), and histone 2A (H2A) revealed that C. albicans contains single orthologs of Bub1 and Sgo1 (Fig 1A), as well as 2 homologous core H2A genes paired with divergently transcribed H2B genes, located on Chromosomes 1 and 3, respectively (Fig 1B)
Because mutation of serine or threonine at position 121 (S/T121) results in chromosome instability in other organisms [19], we hypothesized that deletion of H2A.2 but not H2A.1 would produce the same phenotype in C. albicans and that the evolution of an H2A variant that is resistant to phosphorylation by Bub1 might offer a mechanistic explanation for the chromosome changes observed during the parasexual cycle and upon exposure to aneuploidy-inducing stresses

Summary

Introduction

Aneuploidy is increasingly recognized as an important form of natural variation in eukaryotes. Chromosome segregation during mitosis and meiosis is generally accurate, but environmental. A novel system for rapid evolution in eukaryotes. H.D.M. is an Sr. Investigator of the Chan-Zuckerberg Biohub. S.M. N. is a Burroughs Wellcome Investigator of the Pathogenesis of Infectious Diseases and a Pew Scholar in the Biomedical Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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