A Natural Polymorphism in rDNA Replication Origins Links Origin Activation with Calorie Restriction and Lifespan

Kwan, Elizabeth; Foss, Eric J.; Tsuchiyama, Scott; Alvino, Gina M.; Kruglyak, Leonid; Kaeberlein, Matt; Raghuraman, M. K.; Brewer, Bonita J.; Kennedy, Brian K.; Bedalov, Antonio

doi:10.1371/journal.pgen.1003329

Cited by 104 publications

(115 citation statements)

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“…Based on these findings and others related to the ARS with the rDNA, an alternative model for replicative aging emerged. Specifically, QTL analysis of long-and short-lived yeast isolates identified the rDNA, and specifically the ARS, as a major RLS determinant (Stumpferl et al 2012;Kwan et al 2013). The rDNA-ARS element is relatively inefficient (Miller et al 1999).…”

Section: Sir2-independent Rdna Silencingmentioning

confidence: 99%

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The Nuts and Bolts of Transcriptionally Silent Chromatin in Saccharomyces cerevisiae

2016

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Transcriptional silencing in Saccharomyces cerevisiae occurs at several genomic sites including the silent mating-type loci, telomeres, and the ribosomal DNA (rDNA) tandem array. Epigenetic silencing at each of these domains is characterized by the absence of nearly all histone modifications, including most prominently the lack of histone H4 lysine 16 acetylation. In all cases, silencing requires Sir2, a highly-conserved NAD + -dependent histone deacetylase. At locations other than the rDNA, silencing also requires additional Sir proteins, Sir1, Sir3, and Sir4 that together form a repressive heterochromatin-like structure termed silent chromatin. The mechanisms of silent chromatin establishment, maintenance, and inheritance have been investigated extensively over the last 25 years, and these studies have revealed numerous paradigms for transcriptional repression, chromatin organization, and epigenetic gene regulation. Studies of Sir2-dependent silencing at the rDNA have also contributed to understanding the mechanisms for maintaining the stability of repetitive DNA and regulating replicative cell aging. The goal of this comprehensive review is to distill a wide array of biochemical, molecular genetic, cell biological, and genomics studies down to the "nuts and bolts" of silent chromatin and the processes that yield transcriptional silencing.

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Section: Sir2-independent Rdna Silencingmentioning

confidence: 99%

“…The rDNA-ARS element is relatively inefficient (Miller et al 1999). Polymorphisms in the ARS that increase its initiation activity shorten RLS, perhaps due to genome-wide replication stress caused by titration of factors away from non-rDNA origins (Kwan et al 2013).…”

Section: Sir2-independent Rdna Silencingmentioning

confidence: 99%

The Nuts and Bolts of Transcriptionally Silent Chromatin in Saccharomyces cerevisiae

2016

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“…Another pathway involves Sir2 deacetylase, which can be activated by calorie restriction and which subsequently prolongs life span (Table 1) (148)(149)(150). In addition to the two pathways, rDNA instability or a natural polymorphism in ribosomal ARS has been shown to influence yeast life span independent of ERC accumulation or Sir2 (151,152).…”

Section: Cellular Agingmentioning

confidence: 99%

The Epigenetic Pathways to Ribosomal DNA Silencing

Srivastava

Ahn

2016

Microbiol Mol Biol Rev

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SUMMARYHeterochromatin is the transcriptionally repressed portion of eukaryotic chromatin that maintains a condensed appearance throughout the cell cycle. At sites of ribosomal DNA (rDNA) heterochromatin, epigenetic states contribute to gene silencing and genome stability, which are required for proper chromosome segregation and a normal life span. Here, we focus on recent advances in the epigenetic regulation of rDNA silencing inSaccharomyces cerevisiaeand in mammals, including regulation by several histone modifications and several protein components associated with the inner nuclear membrane within the nucleolus. Finally, we discuss the perturbations of rDNA epigenetic pathways in regulating cellular aging and in causing various types of diseases.

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“…This so-called "Random Replication Gap Problem" (RRGP) is the subject of long-standing speculation, but such gaps have never been experimentally demonstrated (6,7). We have identified a situation in yeast in which repetitive sequences more effectively compete for replication initiation factors, and experimentally limiting this competitive advantage promotes replication of unique regions of the genome and extends lifespan (8).…”

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confidence: 99%

“…As each repeat has its own origin of replication and there are ∼300 non-rDNA origins, ribosomal origins represent 1/3 of all replication origins in the yeast genome. In a cross between two genetically diverse strains of yeast, we identified a naturally occurring single nucleotide polymorphism within the rDNA replication origin (ribosomal DNA Autonomously Replicating Sequence, or rARS) that both decreases origin activity and extends lifespan by 40% (8). By limiting replication initiation at repetitive rDNA, this polymorphism promotes replication elsewhere in the genome.…”

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confidence: 99%

SIR2 suppresses replication gaps and genome instability by balancing replication between repetitive and unique sequences

Foss

Lao

Dalrymple

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Replication gaps that persist into mitosis likely represent important threats to genome stability, but experimental identification of these gaps has proved challenging. We have developed a technique that allows us to explore the dynamics by which genome replication is completed before mitosis. Using this approach, we demonstrate that excessive allocation of replication resources to origins within repetitive regions, induced by SIR2 deletion, leads to persistent replication gaps and genome instability. Conversely, the weakening of replication origins in repetitive regions suppresses these gaps. Given known age-and cancer-associated changes in chromatin accessibility at repetitive sequences, we suggest that replication gaps resulting from misallocation of replication resources underlie age-and disease-associated genome instability.SIR2 | DNA replication | repetitive sequences | replication gaps | ribosomal DNA S taggered initiation of DNA replication, which is common across eukaryotes from fungi to humans, means that, at any given time, in S phase, only a fraction of replication origins is activated. In recent years, a model has emerged to explain this pattern of DNA replication (1, 2). This model assumes that the pool of initiation factors required to fire licensed origins in S phase is limited, and therefore sufficient to fire only a subset of licensed origins at any given time. Licensed origins differ in their ability to recruit factors required for firing, so origins with higher affinity or accessibility fire earlier than those with lower affinity or accessibility. After activating the initial set of origins, firing factors are released, enabling the next set of origins to fire. This results in successive waves of origin activation. Genome replication eventually finishes when areas with the least accessible origins are replicated.In healthy human cells, the least accessible genomic regions consist of repetitive DNA, which represents about half of the genome and tends to be compacted into heterochromatin. However, recent studies suggest widespread opening of hetrochromatin during carcinogenesis and aging (3-5). Such reorganization of chromatin would expose a new suite of origins within repetitive DNA that could potentially compete initiation factors away from unique portions of the genome, thereby disrupting the normal genome-wide hierarchy of replication timing. Increased origin activity within repetitive DNA could thus compromise replication elsewhere in the genome. Given the limited pool of initiation factors, we propose that an increase in density of active origins within repetitive regions could result in a decreased density of such origins in unique regions of the genome, which, when combined with the stochastic nature of origin firing, may occasionally result in replication gaps, i.e., unique regions of the genome that are unable to complete replication before mitosis. This so-called "Random Replication Gap Problem" (RRGP) is the subject of long-standing speculation, but such gaps have never been experim...

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A Natural Polymorphism in rDNA Replication Origins Links Origin Activation with Calorie Restriction and Lifespan

Cited by 104 publications

References 60 publications

The Nuts and Bolts of Transcriptionally Silent Chromatin in Saccharomyces cerevisiae

The Nuts and Bolts of Transcriptionally Silent Chromatin in Saccharomyces cerevisiae

The Epigenetic Pathways to Ribosomal DNA Silencing

SIR2 suppresses replication gaps and genome instability by balancing replication between repetitive and unique sequences

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