H2AX: tailoring histone H2A for chromatin-dependent genomic integrity

2005 ◽  
Vol 83 (4) ◽  
pp. 505-515 ◽  
Author(s):  
Andra Li ◽  
José M Eirín-López ◽  
Juan Ausió
Keyword(s):  
Chromatin Structure ◽  
Histone Variants ◽  
Environmental Damage ◽  
Structural Level ◽  
Histone H2a ◽  
Dna Breaks ◽  
Histone H2ax ◽  
Double Stranded Dna ◽  
Chromatin Remodeling Complexes ◽  
And Function

During the last decade, chromatin research has been focusing on the role of histone variability as a modulator of chromatin structure and function. Histone variability can be the result of either post-translational modifications or intrinsic variation at the primary structure level: histone variants. In this review, we center our attention on one of the most extensively characterized of such histone variants in recent years, histone H2AX. The molecular phylogeny of this variant seems to have run in parallel with that of the major canonical somatic H2A1 in eukaryotes. Functionally, H2AX appears to be mainly associated with maintaining the genome integrity by participating in the repair of the double-stranded DNA breaks exogenously introduced by environmental damage (ionizing radiation, chemicals) or in the process of homologous recombination during meiosis. At the structural level, these processes involve the phosphorylation of serine at the SQE motif, which is present at the very end of the C-terminal domain of H2AX, and possibly other PTMs, some of which have recently started to be defined. We discuss a model to account for how these H2AX PTMs in conjunction with chromatin remodeling complexes (such as INO80 and SWRI) can modify chromatin structure (remodeling) to support the DNA unraveling ultimately required for DNA repair.Key words: H2AX, DNA repair, double-stranded DNA breaks, phosphorylation.

Connection between histone H2A variants and chromatin remodeling complexesThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB’s 51st Annual Meeting – Epigenetics and Chromatin Dynamics, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 87 (1) ◽  
pp. 35-50 ◽  
Author(s):  
Mohammed Altaf ◽  
Andréanne Auger ◽  
Marcela Covic ◽  
Jacques Côté
Keyword(s):  
Chromatin Remodeling ◽  
Chromatin Structure ◽  
Cellular Response ◽  
Peer Review Process ◽  
Histone Variants ◽  
Histone H2a ◽  
Chromatin Dynamics ◽  
Recent Developments ◽  
Chromatin Remodeling Complexes ◽  
And Function

The organization of the eukaryotic genome into chromatin makes it inaccessible to the factors required for gene transcription and DNA replication, recombination, and repair. In addition to histone-modifying enzymes and ATP-dependent chromatin remodeling complexes, which play key roles in regulating many nuclear processes by altering the chromatin structure, cells have developed a mechanism of modulating chromatin structure by incorporating histone variants. These variants are incorporated into specific regions of the genome throughout the cell cycle. H2A.Z, which is an evolutionarily conserved H2A variant, performs several seemingly unrelated and even contrary functions. Another H2A variant, H2A.X, plays a very important role in the cellular response to DNA damage. This review summarizes the recent developments in our understanding of the role of H2A.Z and H2A.X in the regulation of chromatin structure and function, focusing on their functional links with chromatin modifying and remodeling complexes.

scholarly journals Plant Histone HTB (H2B) Variants in Regulating Chromatin Structure and Function

Plants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1435
Author(s):  
Janardan Khadka ◽  
Anat Pesok ◽  
Gideon Grafi
Keyword(s):  
Arabidopsis Thaliana ◽  
Chromatin Structure ◽  
Developmental Stages ◽  
Histone Variants ◽  
Structure And Function ◽  
Core Histone ◽  
Histone H2b ◽  
Histone Proteins ◽  
Genes Encoding ◽  
And Function

Besides chemical modification of histone proteins, chromatin dynamics can be modulated by histone variants. Most organisms possess multiple genes encoding for core histone proteins, which are highly similar in amino acid sequence. The Arabidopsis thaliana genome contains 11 genes encoding for histone H2B (HTBs), 13 for H2A (HTAs), 15 for H3 (HTRs), and 8 genes encoding for histone H4 (HFOs). The finding that histone variants may be expressed in specific tissues and/or during specific developmental stages, often displaying specific nuclear localization and involvement in specific nuclear processes suggests that histone variants have evolved to carry out specific functions in regulating chromatin structure and function and might be important for better understanding of growth and development and particularly the response to stress. In this review, we will elaborate on a group of core histone proteins in Arabidopsis, namely histone H2B, summarize existing data, and illuminate the potential function of H2B variants in regulating chromatin structure and function in Arabidopsis thaliana.

scholarly journals Histone H2A Phosphorylation Controls Crb2 Recruitment at DNA Breaks, Maintains Checkpoint Arrest, and Influences DNA Repair in Fission Yeast

2004 ◽  
Vol 24 (14) ◽  
pp. 6215-6230 ◽  
Author(s):  
Toru M. Nakamura ◽  
Li-Lin Du ◽  
Christophe Redon ◽  
Paul Russell
Keyword(s):  
Dna Repair ◽  
Fission Yeast ◽  
Large Scale ◽  
Dna Helicase ◽  
Histone H2a ◽  
Dna Breaks ◽  
Histone H2ax ◽  
Wide Range ◽  
Carboxy Terminal ◽  
Damaged Dna

ABSTRACT Mammalian ATR and ATM checkpoint kinases modulate chromatin structures near DNA breaks by phosphorylating a serine residue in the carboxy-terminal tail SQE motif of histone H2AX. Histone H2A is similarly regulated in Saccharomyces cerevisiae. The phosphorylated forms of H2AX and H2A, known as γ-H2AX and γ-H2A, are thought to be important for DNA repair, although their evolutionarily conserved roles are unknown. Here, we investigate γ-H2A in the fission yeast Schizosaccharomyces pombe. We show that formation of γ-H2A redundantly requires the ATR/ATM-related kinases Rad3 and Tel1. Mutation of the SQE motif to AQE (H2A-AQE) in the two histone H2A genes caused sensitivity to a wide range of genotoxic agents, increased spontaneous DNA damage, and impaired checkpoint maintenance. The H2A-AQE mutations displayed a striking synergistic interaction with rad22Δ (Rad52 homolog) in ionizing radiation (IR) survival. These phenotypes correlated with defective phosphorylation of the checkpoint proteins Crb2 and Chk1 and a failure to recruit large amounts of Crb2 to damaged DNA. Surprisingly, the H2A-AQE mutations substantially suppressed the IR hypersensitivity of crb2Δ cells by a mechanism that required the RecQ-like DNA helicase Rqh1. We propose that γ-H2A modulates checkpoint and DNA repair through large-scale recruitment of Crb2 to damaged DNA. This function correlates with evidence that γ-H2AX regulates recruitment of several BRCA1 carboxyl terminus domain-containing proteins (NBS1, 53BP1, MDC1/NFBD1, and BRCA1) in mammals.

scholarly journals Short Histone H2A Variants: Small in Stature but not in Function

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 867 ◽  
Author(s):  
Xuanzhao Jiang ◽  
Tatiana A. Soboleva ◽  
David J. Tremethick
Keyword(s):  
Chromatin Structure ◽  
Biochemical Composition ◽  
Histone Variants ◽  
Histone H2a ◽  
The Core ◽  
Unique Protein ◽  
Core Histones ◽  
The Brain ◽  
Fundamental Mechanism ◽  
The Way

The dynamic packaging of DNA into chromatin regulates all aspects of genome function by altering the accessibility of DNA and by providing docking pads to proteins that copy, repair and express the genome. Different epigenetic-based mechanisms have been described that alter the way DNA is organised into chromatin, but one fundamental mechanism alters the biochemical composition of a nucleosome by substituting one or more of the core histones with their variant forms. Of the core histones, the largest number of histone variants belong to the H2A class. The most divergent class is the designated “short H2A variants” (H2A.B, H2A.L, H2A.P and H2A.Q), so termed because they lack a H2A C-terminal tail. These histone variants appeared late in evolution in eutherian mammals and are lineage-specific, being expressed in the testis (and, in the case of H2A.B, also in the brain). To date, most information about the function of these peculiar histone variants has come from studies on the H2A.B and H2A.L family in mice. In this review, we describe their unique protein characteristics, their impact on chromatin structure, and their known functions plus other possible, even non-chromatin, roles in an attempt to understand why these peculiar histone variants evolved in the first place.

scholarly journals Assembly and Disassembly of Nucleosome Core Particles Containing Histone Variants by Human Nucleosome Assembly Protein I

2005 ◽  
Vol 25 (23) ◽  
pp. 10639-10651 ◽  
Author(s):  
Mitsuru Okuwaki ◽  
Kohsuke Kato ◽  
Hideto Shimahara ◽  
Shin-ichi Tate ◽  
Kyosuke Nagata
Keyword(s):  
Chromatin Structure ◽  
Histone Variants ◽  
Biochemical Properties ◽  
Histone H2a ◽  
Nucleosome Assembly ◽  
Active Chromatin ◽  
Nucleosome Core ◽  
Nucleosome Assembly Protein ◽  
Nucleosome Core Particles ◽  
Core Particles

ABSTRACT Histone variants play important roles in the maintenance and regulation of the chromatin structure. In order to characterize the biochemical properties of the chromatin structure containing histone variants, we investigated the dynamic status of nucleosome core particles (NCPs) that were assembled with recombinant histones. We found that in the presence of nucleosome assembly protein I (NAP-I), a histone chaperone, H2A-Barr body deficient (H2A.Bbd) confers the most flexible nucleosome structure among the mammalian histone H2A variants known thus far. NAP-I mediated the efficient assembly and disassembly of the H2A.Bbd-H2B dimers from NCPs. This reaction was accomplished more efficiently when the NCPs contained H3.3, a histone H3 variant known to be localized in the active chromatin, than when the NCPs contained the canonical H3. These observations indicate that the histone variants H2A.Bbd and H3.3 are involved in the formation and maintenance of the active chromatin structure. We also observed that acidic histone binding proteins, TAF-I/SET and B23.1, demonstrated dimer assembly and disassembly activity, but the efficiency of their activity was considerably lower than that of NAP-I. Thus, both the acidic nature of NAP-I and its other functional structure(s) may be essential to mediate the assembly and disassembly of the dimers in NCPs.

scholarly journals The Art of War: harnessing the epigenome against cancer

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 141 ◽  
Author(s):  
Jonathan Nye ◽  
Daniël P. Melters ◽  
Yamini Dalal
Keyword(s):  
Cancer Cells ◽  
Chromatin Structure ◽  
Histone Variants ◽  
Structure And Function ◽  
Histone Chaperones ◽  
Growth And Survival ◽  
Art Of War ◽  
Chromatin Interactions ◽  
And Function ◽  
Target Cancer

Histone chaperones are indispensable regulators of chromatin structure and function. Recent work has shown that they are frequently mis-regulated in cancer, which can have profound consequences on tumor growth and survival. Here, we focus on chaperones for the essential H3 histone variants H3.3 and CENP-A, specifically HIRA, DAXX/ATRX, DEK, and HJURP. This review summarizes recent studies elucidating their roles in regulating chromatin and discusses how cancer-specific chromatin interactions can be exploited to target cancer cells.

scholarly journals Biparental contributions of the H2A.B histone variant control embryonic development in mice

PLoS Biology ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. e3001001
Author(s):  
Antoine Molaro ◽  
Anna J. Wood ◽  
Derek Janssens ◽  
Selina M. Kindelay ◽  
Michael T. Eickbush ◽  
...  
Keyword(s):  
Germ Cells ◽  
Chromatin Structure ◽  
Histone Variants ◽  
Histone H2a ◽  
Biological Functions ◽  
Mammalian Development ◽  
Parental Effect ◽  
Males And Females ◽  
Embryonic Viability ◽  
Effect Gene

Histone variants expand chromatin functions in eukaryote genomes. H2A.B genes are testis-expressed short histone H2A variants that arose in placental mammals. Their biological functions remain largely unknown. To investigate their function, we generated a knockout (KO) model that disrupts all 3 H2A.B genes in mice. We show that H2A.B KO males have globally altered chromatin structure in postmeiotic germ cells. Yet, they do not show impaired spermatogenesis or testis function. Instead, we find that H2A.B plays a crucial role postfertilization. Crosses between H2A.B KO males and females yield embryos with lower viability and reduced size. Using a series of genetic crosses that separate parental and zygotic contributions, we show that the H2A.B status of both the father and mother, but not of the zygote, affects embryonic viability and growth during gestation. We conclude that H2A.B is a novel parental-effect gene, establishing a role for short H2A histone variants in mammalian development. We posit that parental antagonism over embryonic growth drove the origin and ongoing diversification of short histone H2A variants in placental mammals.

Mechanistic and structural insights into histone H2A–H2B chaperone in chromatin regulation

2020 ◽  
Vol 477 (17) ◽  
pp. 3367-3386
Author(s):  
Yan Huang ◽  
Yaxin Dai ◽  
Zheng Zhou
Keyword(s):  
Chromatin Remodeling ◽  
Chromatin Structure ◽  
Current Knowledge ◽  
Histone Variants ◽  
Functional Study ◽  
Histone Chaperones ◽  
Chromatin Regulation ◽  
Histone H2a ◽  
Chromatin Remodeling Complex ◽  
Recent Advances

Histone chaperones include a wide variety of proteins which associate with histones and regulate chromatin structure. The classic H2A–H2B type of histone chaperones, and the chromatin remodeling complex components possessing H2A–H2B chaperone activity, show a broad range of structures and functions. Rapid progress in the structural and functional study of H2A–H2B chaperones extends our knowledge about the epigenetic regulation of chromatin. In this review, we summarize the most recent advances in the understanding of the structure and function of H2A–H2B chaperones that interact with either canonical or variant H2A–H2B dimers. We discuss the current knowledge of the H2A–H2B chaperones, which present no preference for canonical and variant H2A–H2B dimers, describing how they interact with H2A–H2B to fulfill their functions. We also review recent advances of H2A variant-specific chaperones, demarcating how they achieve specific recognition for histone variant H2A.Z and how these interactions regulate chromatin structure by nucleosome editing. We highlight the universal mechanism underlying H2A–H2B dimers recognition by a large variety of histone chaperones. These findings will shed insight into the biological impacts of histone chaperone, chromatin remodeling complex, and histone variants in chromatin regulation.

scholarly journals DHX9-dependent recruitment of BRCA1 to RNA promotes DNA end resection in homologous recombination

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Prasun Chakraborty ◽  
Kevin Hiom
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Rna Polymerase Ii ◽  
Critical Role ◽  
Dna Breaks ◽  
Double Stranded Dna ◽  
Recombination Repair ◽  
Dna End Resection ◽  
End Resection ◽  
Rna Polymerase Ii Transcription

AbstractDouble stranded DNA Breaks (DSB) that occur in highly transcribed regions of the genome are preferentially repaired by homologous recombination repair (HR). However, the mechanisms that link transcription with HR are unknown. Here we identify a critical role for DHX9, a RNA helicase involved in the processing of pre-mRNA during transcription, in the initiation of HR. Cells that are deficient in DHX9 are impaired in the recruitment of RPA and RAD51 to sites of DNA damage and fail to repair DSB by HR. Consequently, these cells are hypersensitive to treatment with agents such as camptothecin and Olaparib that block transcription and generate DSB that specifically require HR for their repair. We show that DHX9 plays a critical role in HR by promoting the recruitment of BRCA1 to RNA as part of the RNA Polymerase II transcription complex, where it facilitates the resection of DSB. Moreover, defects in DHX9 also lead to impaired ATR-mediated damage signalling and an inability to restart DNA replication at camptothecin-induced DSB. Together, our data reveal a previously unknown role for DHX9 in the DNA Damage Response that provides a critical link between RNA, RNA Pol II and the repair of DNA damage by homologous recombination.

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