Deciphering the Enigma of the Histone H2A.Z-1/H2A.Z-2 Isoforms: Novel Insights and Remaining Questions

The replication independent (RI) histone H2A.Z is one of the more extensively studied variant members of the core histone H2A family, which consists of many replication dependent (RD) members. The protein has been shown to be indispensable for survival, and involved in multiple roles from DNA damage to chromosome segregation, replication, and transcription. However, its functional involvement in gene expression is controversial. Moreover, the variant in several groups of metazoan organisms consists of two main isoforms (H2A.Z-1 and H2A.Z-2) that differ in a few (3–6) amino acids. They comprise the main topic of this review, starting from the events that led to their identification, what is currently known about them, followed by further experimental, structural, and functional insight into their roles. Despite their structural differences, a direct correlation to their functional variability remains enigmatic. As all of this is being elucidated, it appears that a strong functional involvement of isoform variability may be connected to development.

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Functions of SMC2 in the Development of Zebrafish Liver

Biomedicines ◽

10.3390/biomedicines9091240 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1240

Author(s):

Xixi Li ◽

Guili Song ◽

Yasong Zhao ◽

Jing Ren ◽

Qing Li ◽

...

Keyword(s):

Dna Damage ◽

Chromosome Segregation ◽

Gene Knockout ◽

Chromosome Organization ◽

Liver Development ◽

Apoptotic Pathway ◽

The Core ◽

Apoptotic Pathways ◽

Structural Maintenance Of Chromosomes ◽

Zebrafish Liver

SMC2 (structural maintenance of chromosomes 2) is the core subunit of condensins, which play a central role in chromosome organization and segregation. However, the functions of SMC2 in embryonic development remain poorly understood, due to the embryonic lethality of homozygous SMC2−/− mice. Herein, we explored the roles of SMC2 in the liver development of zebrafish. The depletion of SMC2, with the CRISPR/Cas9-dependent gene knockout approach, led to a small liver phenotype. The specification of hepatoblasts was unaffected. Mechanistically, extensive apoptosis occurred in the liver of SMC2 mutants, which was mainly associated with the activation of the p53-dependent apoptotic pathway. Moreover, an aberrant activation of a series of apoptotic pathways in SMC2 mutants was involved in the defective chromosome segregation and subsequent DNA damage. Therefore, our findings demonstrate that SMC2 is necessary for zebrafish liver development.

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Novel Functional Residues in the Core Domain of Histone H2B Regulate Yeast Gene Expression and Silencing and Affect the Response to DNA Damage

Molecular and Cellular Biology ◽

10.1128/mcb.00290-10 ◽

2010 ◽

Vol 30 (14) ◽

pp. 3503-3518 ◽

Cited By ~ 14

Author(s):

McKenna N. M. Kyriss ◽

Yi Jin ◽

Isaura J. Gallegos ◽

James A. Sanford ◽

John J. Wyrick

Keyword(s):

Gene Expression ◽

Dna Damage ◽

Structural Model ◽

Dna Lesions ◽

Histone H2b ◽

Core Domain ◽

The Core ◽

Damage Response ◽

Endogenous Genes ◽

Sir Complex

ABSTRACT Previous studies have identified novel modifications in the core fold domain of histone H2B, but relatively little is known about the function of these putative histone modification sites. We have mutated core modifiable residues that are conserved in Saccharomyces cerevisiae histone H2B and characterized the effects of the mutants on yeast silencing, gene expression, and the DNA damage response. We identified three histone H2B core modifiable residues as functionally important. We find that mutating H2B K49 in yeast confers a UV sensitivity phenotype, and we confirm that the homologous residue in human histone H2B is acetylated and methylated in human cells. Our results also indicate that mutating H2B K111 impairs the response to methyl methanesulfonate (MMS)-induced DNA lesions and disrupts telomeric silencing and Sir4 binding. In contrast, mutating H2B R102 enhances silencing at yeast telomeres and the HML silent mating loci and increases Sir4 binding to these regions. The H2B R102A mutant also represses the expression of endogenous genes adjacent to yeast telomeres, which is likely due to the ectopic spreading of the Sir complex in this mutant strain. We propose a structural model by which H2B R102 and K111 regulate the binding of the Sir complex to the nucleosome.

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Cold Shock InducesqnrAExpression inShewanella algae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00991-10 ◽

2010 ◽

Vol 55 (1) ◽

pp. 414-416 ◽

Cited By ~ 22

Author(s):

Hong Bin Kim ◽

Chi Hye Park ◽

Mariah Gavin ◽

George A. Jacoby ◽

David C. Hooper

Keyword(s):

Gene Expression ◽

Dna Damage ◽

Osmotic Stress ◽

Low Temperatures ◽

Cold Shock ◽

Growth Arrest ◽

Qrt Pcr ◽

Reverse Transcription Pcr ◽

Shewanella Algae ◽

Insight Into

ABSTRACTPlasmid-carried quinolone resistance genes, likeqnrA, are widespread inEnterobacteriaceae. To gain insight into its little-understood native functions, we studied the effect of environmental conditions on chromosomalqnrAexpression inShewanella algae. Among conditions of DNA damage, oxidative and osmotic stress, starvation, heat, and cold, only cold shock increased gene expression, as measured by quantitative reverse transcription-PCR (qRT-PCR). Induction was graded and occurred during growth arrest, suggesting thatqnrAmay contribute to the adaptation ofShewanellato low temperatures.

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Histone variants at a glance

Journal of Cell Science ◽

10.1242/jcs.244749 ◽

2021 ◽

Vol 134 (6) ◽

Author(s):

Paul B. Talbert ◽

Steven Henikoff

Keyword(s):

Chromosome Segregation ◽

Transcription Initiation ◽

Histone Variants ◽

Regulation Of Transcription ◽

Histone H2a ◽

Core Particle ◽

Structural Differences ◽

The Common ◽

Histone Core ◽

Nucleosome Stability

ABSTRACT Eukaryotic nucleosomes organize chromatin by wrapping 147 bp of DNA around a histone core particle comprising two molecules each of histone H2A, H2B, H3 and H4. The DNA entering and exiting the particle may be bound by the linker histone H1. Whereas deposition of bulk histones is confined to S-phase, paralogs of the common histones, known as histone variants, are available to carry out functions throughout the cell cycle and accumulate in post-mitotic cells. Histone variants confer different structural properties on nucleosomes by wrapping more or less DNA or by altering nucleosome stability. They carry out specialized functions in DNA repair, chromosome segregation and regulation of transcription initiation, or perform tissue-specific roles. In this Cell Science at a Glance article and the accompanying poster, we briefly examine new insights into histone origins and discuss variants from each of the histone families, focusing on how structural differences may alter their functions.

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The contribution of the budding yeast histone H2A C-terminal tail to DNA-damage responses

Biochemical Society Transactions ◽

10.1042/bst0351519 ◽

2007 ◽

Vol 35 (6) ◽

pp. 1519-1524 ◽

Cited By ~ 17

Author(s):

A.L. Chambers ◽

J.A. Downs

Keyword(s):

Dna Damage ◽

Cellular Response ◽

Budding Yeast ◽

Chromatin Modification ◽

Covalent Modification ◽

Histone H2a ◽

Transcriptional Responses ◽

Dna Lesion ◽

Dna Damage Responses ◽

Insight Into

The cellular response to DNA damage involves extensive interaction with and manipulation of chromatin. This includes the detection and repair of the DNA lesion, but there are also transcriptional responses to DNA damage, involving the up- or down-regulation of numerous genes. Therefore changes to chromatin structure, including covalent modification of histone proteins, are known to occur during DNA-damage responses. One of the most well characterized DNA-damage-responsive chromatin modification events is the phosphorylation of the SQ motif found in the C-terminal tail of histone H2A or the H2AX variant in higher eukaryotes. In the budding yeast, a number of additional residues in this region of histone H2A that contribute to the cellular response to DNA damage have been identified, providing an insight into the nature and complexity of the DNA-damage histone code.

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The centromere comes into focus: from CENP-A nucleosomes to kinetochore connections with the spindle

Open Biology ◽

10.1098/rsob.200051 ◽

2020 ◽

Vol 10 (6) ◽

pp. 200051 ◽

Cited By ~ 5

Author(s):

Kathryn Kixmoeller ◽

Praveen Kumar Allu ◽

Ben E. Black

Keyword(s):

Chromosome Segregation ◽

Molecular Complexes ◽

Molecular Models ◽

Chromosomal Locus ◽

Centromeric Chromatin ◽

Eukaryotic Chromosome ◽

The Core ◽

Histone H3 Variant ◽

Spindle Microtubules ◽

Insight Into

Eukaryotic chromosome segregation relies upon specific connections from DNA to the microtubule-based spindle that forms at cell division. The chromosomal locus that directs this process is the centromere, where a structure called the kinetochore forms upon entry into mitosis. Recent crystallography and single-particle electron microscopy have provided unprecedented high-resolution views of the molecular complexes involved in this process. The centromere is epigenetically specified by nucleosomes harbouring a histone H3 variant, CENP-A, and we review recent progress on how it differentiates centromeric chromatin from the rest of the chromosome, the biochemical pathway that mediates its assembly and how two non-histone components of the centromere specifically recognize CENP-A nucleosomes. The core centromeric nucleosome complex (CCNC) is required to recruit a 16-subunit complex termed the constitutive centromere associated network (CCAN), and we highlight recent structures reported of the budding yeast CCAN. Finally, the structures of multiple modular sub-complexes of the kinetochore have been solved at near-atomic resolution, providing insight into how connections are made to the CCAN on one end and to the spindle microtubules on the other. One can now build molecular models from the DNA through to the physical connections to microtubules.

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UBR2 mediates transcriptional silencing during spermatogenesis via histone ubiquitination

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0910267107 ◽

2010 ◽

Vol 107 (5) ◽

pp. 1912-1917 ◽

Cited By ~ 46

Author(s):

Jee Young An ◽

Eun-A. Kim ◽

Yonghua Jiang ◽

Adriana Zakrzewska ◽

Dong Eun Kim ◽

...

Keyword(s):

Gene Expression ◽

Chromatin Remodeling ◽

Ubiquitin Ligase ◽

Gene Expression Regulation ◽

Transcriptional Silencing ◽

Histone H2a ◽

Y Chromosomes ◽

Proteolytic Pathway ◽

Ubiquitin Conjugating Enzyme ◽

Insight Into

Ubiquitination of histones provides an important mechanism regulating chromatin remodeling and gene expression. Recent studies have revealed ubiquitin ligases involved in histone ubiquitination, yet the responsible enzymes and the function of histone ubiquitination in spermatogenesis remain unclear. We have previously shown that mice lacking the ubiquitin ligase UBR2, one of the recognition E3 components of the N-end rule proteolytic pathway, are infertile associated with meiotic arrest at prophase I. We here show that UBR2 localizes to meiotic chromatin regions, including unsynapsed axial elements linked to chromatin inactivation, and mediates transcriptional silencing via the ubiquitination of histone H2A. UBR2 interacts with the ubiquitin conjugating enzyme HR6B and its substrate H2A and promotes the HR6B–H2A interaction and the HR6B-to-H2A transfer of ubiquitin. UBR2 and ubiquitinated H2A (uH2A) spatiotemporally mark meiotic chromatin regions subject to transcriptional silencing, and UBR2-deficient spermatocytes fail to induce the ubiquitination of H2A during meiosis. UBR2-deficient spermatocytes are profoundly impaired in chromosome-wide transcriptional silencing of genes linked to unsynapsed axes of the X and Y chromosomes. Our findings suggest that insufficiency in UBR2-dependent histone ubiquitination triggers a pachytene checkpoint system, providing a new insight into chromatin remodeling and gene expression regulation.

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Will Love Tear Us Apart: Adapting the Lyrical to the Ludic

CounterText ◽

10.3366/count.2016.0053 ◽

2016 ◽

Vol 2 (2) ◽

pp. 217-235

Author(s):

Gordon Calleja

Keyword(s):

Design Process ◽

Game Design ◽

Digital Games ◽

Design Decisions ◽

The Core ◽

Lyrical Poetry ◽

Insight Into ◽

Made In

This paper gives an insight into the design process of a game adaptation of Joy Division's Love Will Tear Us Apart (1980). It outlines the challenges faced in attempting to reconcile the diverging qualities of lyrical poetry and digital games. In so doing, the paper examines the design decisions made in every segment of the game with a particular focus on the tension between the core concerns of the lyrical work being adapted and established tenets of game design.

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