Chromatin and DNA Replication

MacAlpine, David M.; Almouzni, Geneviève

doi:10.1101/cshperspect.a010207

Cited by 173 publications

(146 citation statements)

References 196 publications

(212 reference statements)

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“…In embryonic stem cells, which also exhibit rapid cycling with short G1, reduced licensing of replication origins creates constitutive replication stress (27). A shift in origin firing toward repetitive sequences likely also occurs during cellular aging in humans, where origins are determined by chromatin accessibility (28,29), and heterochromatic repetitive sequences open up with age (3, 4). Our model, in which replication gaps increase with age as replication resources shift from unique to repetitive sequences, therefore provides a mechanistic explanation for cellular aging that is relevant to organisms from yeast to humans.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…During DNA replication, nucleosomes are removed from templates to permit the passage of DNA polymerases and then added back to recently replicated DNA to reestablish chromatin (72). We infected HFs with HCMV AD169 in the presence or absence of the viral DNA polymerase inhibitor PAA and demonstrated that the drug efficiently inhibited viral DNA replication (Fig.…”

Section: Cd34mentioning

confidence: 99%

Canonical and Variant Forms of Histone H3 Are Deposited onto the Human Cytomegalovirus Genome during Lytic and Latent Infections

Albright

Kalejta

2016

J Virol

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Chromatin is the nucleoprotein complex that protects and compacts eukaryotic genomes. It is responsible for a large part of the epigenetic control of transcription. The genomes of DNA viruses such as human cytomegalovirus (HCMV) are devoid of histones within virions but are chromatinized and epigenetically regulated following delivery to the host cell nucleus. How chromatin is initially assembled on viral genomes and which variant forms of the core histone proteins are deposited are incompletely understood. We monitored the deposition of both ectopically expressed and endogenous histones H3.1 and H3.2 (collectively, H3.1/2) and H3.3 during lytic and latent HCMV infections. Here, we show that they are deposited on HCMV genomes during lytic and latent infections, suggesting similar mechanisms of viral chromatin assembly during the different infection types and indicating that both canonical and variant core histones may be important modulators of infecting viral genomes. We further show that association of both H3.1/2 and H3.3 occurs independent of viral DNA synthesis or de novo viral gene expression, implicating cellular factors and/or virion components in the formation of chromatin on virion-delivered genomes during both lytic and latent infections. IMPORTANCEIt is well established that infecting herpesvirus genomes are chromatinized upon entry into the host cell nucleus. Why or how this occurs is a mystery. It is important to know why they are chromatinized in order to better understand cellular pathogen recognition (DNA sensing) pathways and viral fate determinations (lytic or latent) and to anticipate how artificially modulating chromatinization may impact viral infections. It is important to know how the genomes are chromatinized in order to potentially modulate the process for therapeutic effect. Our work showing that HCMV genomes are loaded with canonical and variant H3 histones during both lytic and latent infections strengthens the hypothesis that chromatinization pathways are similar between the two infection types, implicates virion or cellular factors in this process, and exposes the possibility that histone variants, in addition to posttranslational modification, may impact viral gene expression. These revelations are important to understanding and intelligently intervening in herpesvirus infections.T he large genomes of eukaryotic cells must be highly compacted in order to fit within the restricted volume of the nucleus. To accomplish this, eukaryotic DNA is packaged into a repeating nucleoprotein structure known as chromatin, the basic subunit of which is the nucleosome (1, 2). The core nucleosome particle consists of approximately 146 bp of DNA wrapped nearly twice around a histone hetero-octamer consisting of two copies each of the four core histone proteins H2A, H2B, H3, and H4 (3). Nucleosomes are further compacted into higher-order chromatin fibers through the incorporation of the linker histone H1, other nonhistone proteins, and structural RNA components (4-6).Wrapping DNA in nucleoso...

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“…As the two double helices are synthesized from the two single strands of the mothercell DNA, nucleosomes on the mother-cell DNA strand should also be distributed to both daughter double helices, and completed by de novo nucleosome assembly. In order to ensure the transmission of epigenetic marks to daughter cells, mother-cell nucleosomes should be shared by both newly formed chromosomes, even if the detailed mechanisms of this distribution are still debated (MacAlpine and Almouzni, 2013).…”

Section: Physical Mechanisms Involved In the Initiation Spreadinmentioning

confidence: 99%

The physics of epigenetics

et al. 2016

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In higher organisms, all cells share the same genome, but every cell expresses only a limited and specific set of genes that defines the cell type. During cell division, not only the genome, but also the cell type is inherited by the daughter cells. This intriguing phenomenon is achieved by a variety of processes that have been collectively termed epigenetics: the stable and inheritable changes in gene expression patterns. This article reviews the extremely rich and exquisitely multi-scale physical mechanisms that govern the biological processes behind the initiation, spreading and inheritance of epigenetic states. These include not only the changes in the molecular properties associated with the chemical modifications of DNA and histone proteins, such as methylation and acetylation, but also less conventional changes, typically in the the physics that governs the three-dimensional organization of the genome in cell nuclei. Strikingly, to achieve stability and heritability of epigenetic states, cells take advantage of many different physical principles, such as the universal behavior of polymers and copolymers, the general features of dynamical systems, and the electrostatic and mechanical properties related to chemical modifications of DNA and histones. By putting the complex biological literature under this new light, the emerging picture is that a limited set of general physical rules play a key role in initiating, shaping and transmitting this crucial "epigenetic landscape". This new perspective not only allows to rationalize the normal cellular functions, but also helps to understand the emergence of pathological states, in which the epigenetic landscape becomes dysfunctional.

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Chromatin and DNA Replication

Cited by 173 publications

References 196 publications

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

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

Canonical and Variant Forms of Histone H3 Are Deposited onto the Human Cytomegalovirus Genome during Lytic and Latent Infections

The physics of epigenetics

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