Abstract
DNA repeats, found at the ribosomal DNA locus, telomeres and subtelomeric regions, are unstable sites of eukaryotic genomes. A fine balance between genetic variability and genomic stability tunes plasticity of these chromosomal regions. This tuning mechanism is particularly important for organisms such as microbial pathogens that utilise genome plasticity as a strategy for adaptation. For the first time, we analyse mechanisms promoting genome stability at the rDNA locus and subtelomeric regions in the most common human fungal pathogen: Candida albicans. In this organism, the histone deacetylase Sir2, the master regulator of heterochromatin, has acquired novel functions in regulating genome stability. Contrary to any other systems analysed, C. albicans Sir2 is largely dispensable for repressing recombination at the rDNA locus. We demonstrate that recombination at subtelomeric regions is controlled by a novel DNA element, the TLO Recombination Element, TRE, and by Sir2. While the TRE element promotes high levels of recombination, Sir2 represses this recombination rate. Finally, we demonstrate that, in C. albicans, mechanisms regulating genome stability are plastic as different environmental stress conditions lead to general genome instability and mask the Sir2-mediated recombination control at subtelomeres. Our data highlight how mechanisms regulating genome stability are rewired in C. albicans.
Highlights
Repetitive regions clustered at the rDNA locus and subtelomeric regions are often the most polymorphic and variable regions of eukaryotes genomes [1,2,3,4]
We have shown that the C. albicans NTS region of the rDNA locus is assembled into heterochromatin able to silence an embedded URA3+ marker gene in a silencing reporter strain
To S. cerevisiae, the C. albicans Monopolin complex maintains the transcriptionally silenced state associated with the NTS region of the rDNA locus
Summary
Repetitive regions clustered at the rDNA locus and subtelomeric regions are often the most polymorphic and variable regions of eukaryotes genomes [1,2,3,4]. Repetitive DNA sequences often undergo homologous recombination which can instigate genomic instability. At these locations, moderate genetic variability is beneicial because it generates the genetic diversity driving evolution and allows adaptation to different environmental niches. Excessive genome instability is deleterious and an optimum balance between genome integrity and instability is essential for ensuring itness while permitting adaptation This is important for microbial pathogens that utilise genome plasticity as a strategy to rapidly and reversibly adapt to different environmental niches. Natural isolates exhibit a broad spectrum of genetic and genomic variations including single nucleotide polymorphisms (SNPs), short and long range loss of heterozygosity (LOH) events and whole chromosome aneuploidy [7]. Exposure to hydrogen peroxide (H2O2), mimicking reactive oxygen species by the host’s immune cells, leads to high rates of short range LOH [8]
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