期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 31, 页码 9674-9679出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1505015112
关键词
ribosomal DNA; homologous recombination; Sir2; copy number variation; TOR
资金
- Wellcome Trust [088335, 093735]
- MRC studentship
- Erwin Schroedinger fellowship from Austrian Science Fund (FWF) (Austria) [J 3341]
- Austrian Science Fund (FWF) [J3341] Funding Source: Austrian Science Fund (FWF)
- BBSRC [BBS/E/B/0000H247, BBS/E/B/0000M755, BBS/E/B/000C0401] Funding Source: UKRI
- Austrian Science Fund (FWF) [J 3341] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BBS/E/B/000C0401, BBS/E/B/0000H247, BBS/E/B/0000M755] Funding Source: researchfish
- Medical Research Council [1519969] Funding Source: researchfish
- The Francis Crick Institute [10134] Funding Source: researchfish
Repeated regions are widespread in eukaryotic genomes, and key functional elements such as the ribosomal DNA tend to be formed of high copy repeated sequences organized in tandem arrays. In general, high copy repeats are remarkably stable, but a number of organisms display rapid ribosomal DNA amplification at specific times or under specific conditions. Here we demonstrate that target of rapamycin (TOR) signaling stimulates ribosomal DNA amplification in budding yeast, linking external nutrient availability to ribosomal DNA copy number. We show that ribosomal DNA amplification is regulated by three histone deacetylases: Sir2, Hst3, and Hst4. These enzymes control homologous recombination-dependent and nonhomologous recombination-dependent amplification pathways that act in concert to mediate rapid, directional ribosomal DNA copy number change. Amplification is completely repressed by rapamycin, an inhibitor of the nutrient-responsive TOR pathway; this effect is separable from growth rate and is mediated directly through Sir2, Hst3, and Hst4. Caloric restriction is known to up-regulate expression of nicotin amidase Pnc1, an enzyme that enhances Sir2, Hst3, and Hst4 activity. In contrast, normal glucose concentrations stretch the ribosome synthesis capacity of cells with low ribosomal DNA copy number, and we find that these cells show a previously unrecognized transcriptional response to caloric excess by reducing PNC1 expression. PNC1 down-regulation forms a key element in the control of ribosomal DNA amplification as overexpression of PNC1 substantially reduces ribosomal DNA amplification rate. Our results reveal how a signaling pathway can orchestrate specific genome changes and demonstrate that the copy number of repetitive DNA can be altered to suit environmental conditions.
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