scholarly journals Chromatin and Nuclear Dynamics in the Maintenance of Replication Fork Integrity

2021 ◽  
Vol 12 ◽  
Author(s):  
Jack Wootton ◽  
Evi Soutoglou
Keyword(s):  
Replication Timing ◽  
Histone Variants ◽  
Multiple Roles ◽  
Heterochromatin Protein 1 ◽  
Nuclear Dynamics ◽  
Post Translational Modifications ◽  
Topologically Associated Domains ◽  
Nuclear Environment ◽  
The Many ◽  
Stalled Replication Forks

Replication of the eukaryotic genome is a highly regulated process and stringent control is required to maintain genome integrity. In this review, we will discuss the many aspects of the chromatin and nuclear environment that play key roles in the regulation of both unperturbed and stressed replication. Firstly, the higher order organisation of the genome into A and B compartments, topologically associated domains (TADs) and sub-nuclear compartments has major implications in the control of replication timing. In addition, the local chromatin environment defined by non-canonical histone variants, histone post-translational modifications (PTMs) and enrichment of factors such as heterochromatin protein 1 (HP1) plays multiple roles in normal S phase progression and during the repair of replicative damage. Lastly, we will cover how the spatial organisation of stalled replication forks facilitates the resolution of replication stress.

The nucleosome: a little variation goes a long wayThis paper is one of a selection of papers published in this Special Issue, entitled 27th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process.

2006 ◽  
Vol 84 (4) ◽  
pp. 505-507 ◽  
Author(s):  
Emily Bernstein ◽  
Sandra B. Hake
Keyword(s):  
Peer Review Process ◽  
Gene Activation ◽  
Epigenetic Inheritance ◽  
Histone Variants ◽  
Post Translational Modifications ◽  
Chromatin Compaction ◽  
Cellular Processes ◽  
Chromatin Template ◽  
Mitosis And Meiosis ◽  
Selection Of

Changes in the overall structure of chromatin are essential for the proper regulation of cellular processes, including gene activation and silencing, DNA repair, chromosome segregation during mitosis and meiosis, X chromosome inactivation in female mammals, and chromatin compaction during apoptosis. Such alterations of the chromatin template occur through at least 3 interrelated mechanisms: post-translational modifications of histones, ATP-dependent chromatin remodeling, and the incorporation (or replacement) of specialized histone variants into chromatin. Of these mechanisms, the exchange of variants into and out of chromatin is the least well understood. However, the exchange of conventional histones for variant histones has distinct and profound consequences within the cell. This review focuses on the growing number of mammalian histone variants, their particular biological functions and unique features, and how they may affect the structure of the nucleosome. We propose that a given nucleosome might not consist of heterotypic variants, but rather, that only specific histone variants come together to form a homotypic nucleosome, a hypothesis that we refer to as the nucleosome code. Such nucleosomes might in turn participate in marking specific chromatin domains that may contribute to epigenetic inheritance.

scholarly journals The Protective Role of Dormant Origins in Response to Replicative Stress

2018 ◽  
Vol 19 (11) ◽  
pp. 3569 ◽  
Author(s):  
Lilas Courtot ◽  
Jean-Sébastien Hoffmann ◽  
Valérie Bergoglio
Keyword(s):  
Dna Replication ◽  
Mammalian Cells ◽  
Genome Stability ◽  
Replication Timing ◽  
Protective Role ◽  
Entire Genome ◽  
Replicative Stress ◽  
A Cell ◽  
The Many

Genome stability requires tight regulation of DNA replication to ensure that the entire genome of the cell is duplicated once and only once per cell cycle. In mammalian cells, origin activation is controlled in space and time by a cell-specific and robust program called replication timing. About 100,000 potential replication origins form on the chromatin in the gap 1 (G1) phase but only 20–30% of them are active during the DNA replication of a given cell in the synthesis (S) phase. When the progress of replication forks is slowed by exogenous or endogenous impediments, the cell must activate some of the inactive or “dormant” origins to complete replication on time. Thus, the many origins that may be activated are probably key to protect the genome against replication stress. This review aims to discuss the role of these dormant origins as safeguards of the human genome during replicative stress.

scholarly journals Nucleus, Mitochondrion, or Reticulum? STAT3 à La Carte

2018 ◽  
Vol 19 (9) ◽  
pp. 2820 ◽  
Author(s):  
Lidia Avalle ◽  
Valeria Poli
Keyword(s):  
Energy Production ◽  
Energy Homeostasis ◽  
Multiple Roles ◽  
Pharmaceutical Companies ◽  
Signal Transducer ◽  
Post Translational Modifications ◽  
Pathological Conditions ◽  
Different Types ◽  
Tumor Transformation ◽  
Context Specific

The transcription factor signal transducer and activator of transcription (STAT)3 mediates the functions of cytokines, growth factors, and oncogenes under both physiological and pathological conditions. Uncontrolled/constitutive STAT3 activity is often detected in tumors of different types, where its role is mostly that of an oncogene, contributing in multiple ways to tumor transformation, growth, and progression. For this reason, many laboratories and pharmaceutical companies are making efforts to develop specific inhibitors. However, STAT3 has also been shown to act as a tumor suppressor in a number of cases, suggesting that its activity is strongly context-specific. Here, we discuss the bases that can explain the multiple roles of this factor in both physiological and pathological contexts. In particular, we focus on the following four features: (i) the distinct properties of the STAT3α and β isoforms; (ii) the multiple post-translational modifications (phosphorylation on tyrosine or serine, acetylation and methylation on different residues, and oxidation and glutathionylation) that can affect its activities downstream of multiple different signals; (iii) the non-canonical functions in the mitochondria, contributing to the maintenance of energy homeostasis under stress conditions; and (iv) the recently discovered functions in the endoplasmic reticulum, where STAT3 contributes to the regulation of calcium homeostasis, energy production, and apoptosis.

How Media Shapes the Public Discourse and Influences Health

2020 ◽  
pp. 23-35
Author(s):  
Alonzo L. Plough
Keyword(s):  
News Media ◽  
Public Discourse ◽  
Multiple Roles ◽  
Health Issues ◽  
The Public ◽  
Inaccurate Information ◽  
Modern Media ◽  
Multiple Media ◽  
American Society ◽  
The Many

This chapter describes the multiple roles of modern media in determining not only what consumers know, but also how and what they think. The exponential growth of ideologically driven cable channels and social media, dovetailing with cutbacks in newspaper staffing and coverage, point to the many ways that the power and reach of media are shifting even as they continue to reshape American society and norms. In this environment, multiple media compete for viewers, readers, and listeners who will click on their websites, buy their products, sign their petitions, and often accept their spin, especially if it reinforces personal perspectives. Thoughtful information about complex public health issues is easily lost in that context, leading too many people to base their decision-making on incomplete, biased, and even inaccurate information. For the news media to help build a Culture of Health, people need to understand how it works, what it does, and how it can be used for widespread benefit.

scholarly journals Analysis of the structural variability of topologically associated domains as revealed by Hi-C

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Natalie Sauerwald ◽  
Akshat Singhal ◽  
Carl Kingsford
Keyword(s):  
Structural Changes ◽  
Chromosome Structure ◽  
Three Dimensional ◽  
Replication Timing ◽  
Building Blocks ◽  
Structural Features ◽  
Genetic Sequence ◽  
Experimental Variation ◽  
Topologically Associated Domains ◽  
Integral Role

Abstract Three-dimensional chromosome structure plays an integral role in gene expression and regulation, replication timing, and other cellular processes. Topologically associated domains (TADs), building blocks of chromosome structure, are genomic regions with higher contact frequencies within the region than outside the region. A central question is the degree to which TADs are conserved or vary between conditions. We analyze 137 Hi-C samples from 9 studies under 3 measures to quantify the effects of various sources of biological and experimental variation. We observe significant variation in TAD sets between both non-replicate and replicate samples, and provide initial evidence that this variability does not come from genetic sequence differences. The effects of experimental protocol differences are also measured, demonstrating that samples can have protocol-specific structural changes, but that TADs are generally robust to lab-specific differences. This study represents a systematic quantification of key factors influencing comparisons of chromosome structure, suggesting significant variability and the potential for cell-type-specific structural features, which has previously not been systematically explored. The lack of observed influence of heredity and genetic differences on chromosome structure suggests that factors other than the genetic sequence are driving this structure, which plays an important role in human disease and cellular functioning.

scholarly journals Exo1 phosphorylation inhibits exonuclease activity and prevents fork collapse in rad53 mutants independently of the 14-3-3 proteins

2020 ◽  
Vol 48 (6) ◽  
pp. 3053-3070
Author(s):  
Esther C Morafraile ◽  
Alberto Bugallo ◽  
Raquel Carreira ◽  
María Fernández ◽  
Cristina Martín-Castellanos ◽  
...  
Keyword(s):  
Genome Stability ◽  
Nuclease Activity ◽  
S Phase ◽  
Exonuclease Activity ◽  
Replication Forks ◽  
Post Translational Modifications ◽  
Replicative Stress ◽  
Stalled Replication Forks ◽  
Maintain Genome Stability ◽  
Specific Contribution

Abstract The S phase checkpoint is crucial to maintain genome stability under conditions that threaten DNA replication. One of its critical functions is to prevent Exo1-dependent fork degradation, and Exo1 is phosphorylated in response to different genotoxic agents. Exo1 seemed to be regulated by several post-translational modifications in the presence of replicative stress, but the specific contribution of checkpoint-dependent phosphorylation to Exo1 control and fork stability is not clear. We show here that Exo1 phosphorylation is Dun1-independent and Rad53-dependent in response to DNA damage or dNTP depletion, and in both situations Exo1 is similarly phosphorylated at multiple sites. To investigate the correlation between Exo1 phosphorylation and fork stability, we have generated phospho-mimic exo1 alleles that rescue fork collapse in rad53 mutants as efficiently as exo1-nuclease dead mutants or the absence of Exo1, arguing that Rad53-dependent phosphorylation is the mayor requirement to preserve fork stability. We have also shown that this rescue is Bmh1–2 independent, arguing that the 14-3-3 proteins are dispensable for fork stabilization, at least when Exo1 is downregulated. Importantly, our results indicated that phosphorylation specifically inhibits the 5' to 3'exo-nuclease activity, suggesting that this activity of Exo1 and not the flap-endonuclease, is the enzymatic activity responsible of the collapse of stalled replication forks in checkpoint mutants.

Sketching across design domains: Roles and formalities

2012 ◽  
Vol 26 (3) ◽  
pp. 245-266 ◽  
Author(s):  
Claudia Eckert ◽  
Alan Blackwell ◽  
Martin Stacey ◽  
Christopher Earl ◽  
Luke Church
Keyword(s):  
Idea Generation ◽  
Multiple Roles ◽  
Specific Design ◽  
Design Processes ◽  
Different Types ◽  
The Many ◽  
Design Ideas

AbstractTo complement studies on design sketching within particular phases of design processes in specific design domains, this paper analyzes descriptions of design processes given by designers from a wide variety of fields. This research forms part of a wider project on comparisons across design domains and draws attention to the many types and properties of sketches in different contexts. Further, it focuses on the multiple roles that sketching can take in idea generation, as well as in reasoning and communicating design ideas. In particular this paper examines how the different types and roles of sketches can be more or less formal and how this can lead to misunderstandings.

scholarly journals Evolutionary origins and diversification of testis-specific short histone H2A variants in mammals

2017 ◽  
Author(s):  
Antoine Molaro ◽  
Janet M. Young ◽  
Harmit S. Malik
Keyword(s):  
Genome Stability ◽  
Histone Variants ◽  
Histone Variant ◽  
Histone H2a ◽  
Genetic Conflict ◽  
Post Translational Modifications ◽  
Evolutionary Origins ◽  
Male Germline ◽  
Early Diversification ◽  
Canonical Histone

Eukaryotic genomes must accomplish the tradeoff between compact packaging for genome stability and inheritance, and accessibility for gene expression. They do so using post-translational modifications of four ancient canonical histone proteins (H2A, H2B, H3 and H4), and by deploying histone variants with specialized chromatin functions. While some histone variants are highly conserved across eukaryotes, others carry out lineage-specific functions. Here, we characterize the evolution of male germline-specific “short H2A variants”, which wrap shorter DNA fragments than canonical H2A. In addition to three previously described H2A.B, H2A.L and H2A.P variants, we describe a novel, extremely short H2A histone variant: H2A.Q. We show that H2A.B, H2A.L, H2A.P and H2A.Q are most closely related to a novel, more canonical mmH2A variant found only in monotremes and marsupials. Using phylogenomics, we trace the origins and early diversification of short histone variants into four distinct clades to the ancestral X chromosome of placental mammals. We show that short H2A variants further diversified by repeated lineage-specific amplifications and losses, including pseudogenization of H2A.L in many primates. We also uncover evidence for concerted evolution of H2A.B and H2A.L genes by gene conversion in many species, involving loci separated by large distances. Finally, we find that short H2As evolve more rapidly than any other histone variant, with evidence that positive selection has acted upon H2A.P in primates. Based on their X chromosomal location and pattern of genetic innovation, we speculate that short H2A histone variants are engaged in a form of genetic conflict involving the mammalian sex chromosomes.

scholarly journals Epigenetic Regulation of Myogenesis: Focus on the Histone Variants

2021 ◽  
Vol 22 (23) ◽  
pp. 12727
Author(s):  
Joana Esteves de Lima ◽  
Frédéric Relaix
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Epigenetic Regulation ◽  
Muscle Development ◽  
Regulation Of Gene Expression ◽  
Histone Variants ◽  
Myoblast Differentiation ◽  
Post Translational Modifications ◽  
Differentiation Status

Skeletal muscle development and regeneration rely on the successive activation of specific transcription factors that engage cellular fate, promote commitment, and drive differentiation. Emerging evidence demonstrates that epigenetic regulation of gene expression is crucial for the maintenance of the cell differentiation status upon division and, therefore, to preserve a specific cellular identity. This depends in part on the regulation of chromatin structure and its level of condensation. Chromatin architecture undergoes remodeling through changes in nucleosome composition, such as alterations in histone post-translational modifications or exchange in the type of histone variants. The mechanisms that link histone post-translational modifications and transcriptional regulation have been extensively evaluated in the context of cell fate and differentiation, whereas histone variants have attracted less attention in the field. In this review, we discuss the studies that have provided insights into the role of histone variants in the regulation of myogenic gene expression, myoblast differentiation, and maintenance of muscle cell identity.

scholarly journals The Chd1 chromatin remodeler shifts hexasomes unidirectionally

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Robert F Levendosky ◽  
Anton Sabantsev ◽  
Sebastian Deindl ◽  
Gregory D Bowman
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Histone Variants ◽  
Chromatin Remodeler ◽  
Post Translational Modifications ◽  
Pol Ii ◽  
Specific Orientation ◽  
Chromatin Reorganization

Despite their canonical two-fold symmetry, nucleosomes in biological contexts are often asymmetric: functionalized with post-translational modifications (PTMs), substituted with histone variants, and even lacking H2A/H2B dimers. Here we show that the Widom 601 nucleosome positioning sequence can produce hexasomes in a specific orientation on DNA, providing a useful tool for interrogating chromatin enzymes and allowing for the generation of nucleosomes with precisely defined asymmetry. Using this methodology, we demonstrate that the Chd1 chromatin remodeler from Saccharomyces cerevisiae requires H2A/H2B on the entry side for sliding, and thus, unlike the back-and-forth sliding observed for nucleosomes, Chd1 shifts hexasomes unidirectionally. Chd1 takes part in chromatin reorganization surrounding transcribing RNA polymerase II (Pol II), and using asymmetric nucleosomes we show that ubiquitin-conjugated H2B on the entry side stimulates nucleosome sliding by Chd1. We speculate that biased nucleosome and hexasome sliding due to asymmetry contributes to the packing of arrays observed in vivo.

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