title: Spontaneous rDNA copy number variation modulates Sir2 levels and epigenetic gene silencing.
abstract: We show that in budding yeast large rDNA deletions arise frequently and cause an increase in telomeric and mating-type gene silencing proportional to repeat loss. Paradoxically, this increase in silencing is correlated with a highly specific down-regulation of SIR2, which encodes a deacetylase enzyme required for silencing. These apparently conflicting observations suggest that a large nucleolar pool of Sir2 is released upon rDNA loss and made available for telomeric and HM silencing, as well as down-regulation of SIR2 itself. Indeed, we present evidence for a reduction in the fraction of Sir2 colocalizing with the nucleolar marker Nop1, and for SIR2 autoregulation. Despite a decrease in the fraction of nucleolar Sir2, and in overall Sir2 protein levels, short rDNA strains display normal rDNA silencing and a lifespan indistinguishable from wild type. These observations reveal an unexpectedly large clonal variation in rDNA cluster size and point to the existence of a novel regulatory circuit, sensitive to rDNA copy number, that balances nucleolar and nonnucleolar pools of Sir2 protein.
authors.affiliation: Department of Molecular Biology and NCCR Program "Frontiers in Genetics", University of Geneva, Sciences III, 30, quai Ernest-Ansermet, CH-1211, Geneva 4, Switzerland.
authors.forename: Agnès H
authors.initials: AH
authors.lastname: Michel
authors.forename: Benoît
authors.initials: B
authors.lastname: Kornmann
authors.forename: Karine
authors.initials: K
authors.lastname: Dubrana
authors.forename: David
authors.initials: D
authors.lastname: Shore
mesh_terms: D004271:DNA, Fungal / Q000378:metabolism*; D004275:DNA, Ribosomal / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology*; D044127:Epigenesis, Genetic; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology*; D006655:Histone Deacetylases / Q000235:genetics / Q000502:physiology*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020718:Ribonucleoproteins, Small Nucleolar / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology*; D056565:Sirtuin 2; D037761:Sirtuins / Q000235:genetics / Q000502:physiology*; D013045:Species Specificity; D016615:Telomere / Q000502:physiology
chemical_list: D004271:DNA, Fungal; D004275:DNA, Ribosomal; C064793:NOP1 protein, S cerevisiae; D009687:Nuclear Proteins; D020718:Ribonucleoproteins, Small Nucleolar; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases