Regulation of ribosomal DNA amplification by the TOR pathway

Jack, Carmen V.; Cruz, Cristina; Hull, Ryan M.; Keller, Markus A.; Ralser, Markus; Houseley, Jonathan

doi:10.1073/pnas.1505015112

Cited by 83 publications

(95 citation statements)

References 49 publications

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“…Secondly, nat4Δ enhanced RENT binding at the rDNA locus (Fig B) and greater RENT binding has been previously connected to increased rDNA stability . Thirdly, the above possibility was supported by the fact that nat4Δ induces PNC1 (Fig ), whose overexpression has already been correlated to reduced ribosomal DNA amplification through enhanced Sir2 activity and that nat4Δ ‐mediated longevity is dependent on the presence of Sir2 (Fig D). However, despite all the above indications, we did not find a connection between nat4Δ ‐induced longevity and altered rDNA recombination (Fig C), suggesting that Nat4 and N‐acH4 function within a CR pathway that does not implicate rDNA stability (Fig ).…”

Section: Discussionmentioning

confidence: 60%

Loss of Nat4 and its associated histone H4 N‐terminal acetylation mediates calorie restriction‐induced longevity

et al. 2016

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Changes in histone modifications are an attractive model through which environmental signals, such as diet, could be integrated in the cell for regulating its lifespan. However, evidence linking dietary interventions with specific alterations in histone modifications that subsequently affect lifespan remains elusive. We show here that deletion of histone N‐alpha‐terminal acetyltransferase Nat4 and loss of its associated H4 N‐terminal acetylation (N‐acH4) extend yeast replicative lifespan. Notably, nat4Δ‐induced longevity is epistatic to the effects of calorie restriction (CR). Consistent with this, (i) Nat4 expression is downregulated and the levels of N‐acH4 within chromatin are reduced upon CR, (ii) constitutive expression of Nat4 and maintenance of N‐acH4 levels reduces the extension of lifespan mediated by CR, and (iii) transcriptome analysis indicates that nat4Δ largely mimics the effects of CR, especially in the induction of stress‐response genes. We further show that nicotinamidase Pnc1, which is typically upregulated under CR, is required for nat4Δ‐mediated longevity. Collectively, these findings establish histone N‐acH4 as a regulator of cellular lifespan that links CR to increased stress resistance and longevity.

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Section: Discussionmentioning

confidence: 60%

Loss of Nat4 and its associated histone H4 N‐terminal acetylation mediates calorie restriction‐induced longevity

et al. 2016

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“…In most eukaryotes, the rDNA locus is very plastic: the number of rDNA units changes in response to nutrients availability (42). However, excessive plasticity is deleterious and regulatory mechanisms have been evolved to ensure rDNA integrity.…”

Section: Discussionmentioning

confidence: 99%

Sir2 regulates stability of repetitive domains differentially in the human fungal pathogenCandida albicans

et al. 2016

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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.

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“…These hotspots, often designated as common fragile sites, may occur in large, late replicating genes, and be a function of inter-origin distance [77][78][79] . Local transcription at the rDNA locus leads to rDNA amplification, and is thought to be regulated in response to the environment [80] . Transcription of the CUP1 locus in response to environmental copper leads to promoter activity that further destabilizes stalled replication forks and generates CNVs [81] .…”

Section: Surprisingly Gap1 Gene Amplifications Occurring Between Thementioning

confidence: 99%

Single-cell copy number variant detection reveals the dynamics and diversity of adaptation

Lauer

Avecilla

Spealman

et al. 2018

Preprint

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Copy number variants (CNVs) are a pervasive, but understudied source of genetic variation and evolutionary potential. Long-term evolution experiments in chemostats provide an ideal system for studying the molecular processes underlying CNV formation and the temporal dynamics of de novo CNVs. Here, we developed a fluorescent reporter to monitor gene amplifications and deletions at a specific locus with single-cell resolution. Using a CNV reporter in nitrogen-limited chemostats, we find that GAP1 CNVs are repeatedly generated and selected during the early stages of adaptive evolution resulting in predictable dynamics of CNV selection. However, subsequent diversification of populations defines a second phase of evolutionary dynamics that cannot be predicted. Using whole genome sequencing, we identified a variety of GAP1 CNVs that vary in size and copy number. Despite GAP1 's proximity to tandem repeats that facilitate intrachromosomal recombination, we find that non-allelic homologous recombination (NAHR) between flanking tandem repeats occurs infrequently. Rather, breakpoint characterization revealed that for at least 50% of GAP1 CNVs, origin-dependent inverted-repeat amplification (ODIRA), a DNA replication mediated process, is the likely mechanism. We also find evidence that ODIRA generates DUR3 CNVs, indicating that it may be a common mechanism of gene amplification. We combined the CNV reporter with barcode lineage tracking and found that 10 3 -10 4 independent CNV-containing lineages initially compete within populations, which results in extreme clonal interference. Our study introduces a novel means of studying CNVs in heterogeneous cell populations and provides insight into the underlying dynamics of CNVs in evolution.condition [32,33] . A high rate of CNV formation suggests that multiple, independent CNV-containing lineages may compete during adaptive evolution resulting in clonal interference, which is characteristic of large, evolving populations [29,[34][35][36] . However, the extent of clonal interference among CNV-containing lineages is unknown.The general amino acid permease, GAP1 , is ideally suited to studying the role of CNVs in adaptive evolution. GAP1 encodes a high-affinity transporter for all naturally occurring amino acids and analogues, and it is highly expressed in nitrogen-poor conditions [37,38] . We have previously shown that two classes of CNVs are selected at the GAP1 locus in S. cerevisiae : amplification alleles in glutamine and glutamate-limited chemostats and deletion alleles in ureaand allantoin-limited chemostats [24,25] . GAP1 CNVs are also found in natural populations.Multiple, tandem copies of GAP1 have been identified in wild populations of the nectar yeast, Metschnikowia reukaufii , which result in a competitive advantage over other microbes when amino acids are scarce [39] . As a frequent target of selection in adverse environments in both experimental and natural populations, GAP1 is a model locus for studying the dynamics and mechanisms underlying both gene amplification a...

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Regulation of ribosomal DNA amplification by the TOR pathway

Cited by 83 publications

References 49 publications

Loss of Nat4 and its associated histone H4 N‐terminal acetylation mediates calorie restriction‐induced longevity

Loss of Nat4 and its associated histone H4 N‐terminal acetylation mediates calorie restriction‐induced longevity

Sir2 regulates stability of repetitive domains differentially in the human fungal pathogenCandida albicans

Single-cell copy number variant detection reveals the dynamics and diversity of adaptation

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