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PubMed1984

Evidence for a human histone gene cluster containing H2B and H2A pseudogenes.

Not all members of the human histone gene family are functional. We have isolated a human H2B pseudogene that contains alterations in the protein-coding sequences as well as in the 3' and 5' flanking sequences that preclude expression of a functional H2B histone protein. There are three modifications in the amino acid-coding region: a single-base deletion producing a frame shift, a single-base substitution resulting in a codon change from serine to tryptophan (an amino acid not present in histones), and the absence of a stop codon. Analysis of nucleotide sequences upstream from the AUG start signal indicates the absence of a "TATA" box and other putative consensus regulatory sequences. In the 3' flanking region, a highly conserved block of 22 nucleotides that exhibits hyphenated dyad symmetry is displaced downstream. Within the same genomic segment, the adjacent H2A histone gene is missing 12 nucleotides, resulting in a deletion of four amino acids in a highly conserved region of the protein.

Amino Acid Sequence↗
PubMed2004

Histone H2A ubiquitination does not preclude histone H1 binding, but it facilitates its association with the nucleosome.

Histone H2A ubiquitination is a bulky posttranslational modification that occurs at the vicinity of the binding site for linker histones in the nucleosome. Therefore, we took several experimental approaches to investigate the role of ubiquitinated H2A (uH2A) in the binding of linker histones. Our results showed that uH2A was present in situ in histone H1-containing nucleosomes. Notably in vitro experiments using nucleosomes reconstituted onto 167-bp random sequence and 208-bp (5 S rRNA gene) DNA fragments showed that ubiquitination of H2A did not prevent binding of histone H1 but it rather enhanced the binding of this histone to the nucleosome. We also showed that ubiquitination of H2A did not affect the positioning of the histone octamer in the nucleosome in either the absence or the presence of linker histones.

Animals↗
PubMed2005

Phosphorylation of Ser28 in histone H3 mediated by mixed lineage kinase-like mitogen-activated protein triple kinase alpha.

The mitogen-activated protein kinase cascades elicit modification of chromatin proteins such as histone H3 by phosphorylation concomitant with gene activation. Here, we demonstrate for the first time that the mixed lineage kinase-like mitogen-activated protein triple kinase (MLTK)-alpha phosphorylates histone H3 at Ser28. MLTK-alpha but neither a kinase-negative mutant of MLTK-alpha nor MLTK-beta interacted with and phosphorylated histone H3 in vivo and in vitro. When overexpressed in 293T or JB6 Cl41 cells, MLTK-alpha phosphorylated histone H3 at Ser28 but not at Ser10. The interaction between MLTK-alpha and histone H3 was enhanced by stimulation with ultraviolet B light (UVB) or epidermal growth factor (EGF), which resulted in the accumulation of MLTK-alpha in the nucleus. UVB- or EGF-induced phosphorylation of histone H3 at Ser28 was not affected by PD 98059, a MEK inhibitor, or SB 202190, a p38 kinase inhibitor, in MLTK-alpha-overexpressing JB6 Cl41 cells. Significantly, UVB- or EGF-induced phosphorylation of histone H3 at Ser28 was blocked by small interfering RNA of MLTK-alpha. The inhibition of histone H3 phosphorylation at Ser28 in the MLTK-alpha knock-down JB6 Cl41 cells was not due to a defect in mitogen- and stress-activated protein kinase 1 or 90-kDa ribosomal S6 kinase (p90RSK) activity. In summary, these results illustrate that MLTK-alpha plays a key role in the UVB- and EGF-induced phosphorylation of histone H3 at Ser28, suggesting that MLTK-alpha might be a new histone H3 kinase at the level of mitogen-activated protein kinase kinase kinases.

Amino Acid Sequence↗
PubMed2026

Linker Histone H1 Phosphorylation Promotes DNA Damage Repair during Replication Stress.

DNA replication fidelity depends on the integrity of the replication fork to prevent DNA damage and preserve genome stability. Disruptions to this process can trigger replication stress, leading to the accumulation of single-strand DNA (ssDNA) and double-strand breaks (DSBs), which drive mutagenesis and ultimately contribute to disease. While the roles of core histones and their post-translational modifications in this context have been more well-studied, far less is known about how linker histones regulate the replication stress response. Here, we demonstrate that the S-phase-phosphorylated form of the linker histone H1 (pH1) plays a key role in DNA damage repair at collapsed replication forks, both in vitro and in cells. Using phosphomimic and phosphonull H1 mutants, we show that phosphorylation enhances H1 assembly with ssDNA. Utilizing intein chemistry for the site-specific incorporation of a photocrosslinker to the C-terminus of H1, we map the direct interactors of H1. We identify phosphorylated H1 at replication forks, where it engages replication machinery and DNA damage response factors, including Histone PARylation Factor 1 (HPF1). We further demonstrate that ssDNA induces pH1-HPF1 interactions that promote liquid-like assemblies, correlating with reduced DNA damage and histone PARylation. Consistent with this role, reduction of total H1 increases cellular sensitivity to DNA damage, a phenotype that is partially rescued by reintroduction of H1.4. Together, these findings establish pH1 as a new regulator of DNA damage repair at collapsed replication forks through the controlled sequestration of repair factors.

Journal Article↗
PubMed2003

A nucleosomal function for IkappaB kinase-alpha in NF-kappaB-dependent gene expression.

NF-kappaB is a principal transcriptional regulator of diverse cytokine-mediated processes and is tightly controlled by the IkappaB kinase complex (IKK-alpha/beta/gamma). IKK-beta and IKK-gamma are critical for cytokine-induced NF-kappaB function, whereas IKK-alpha is thought to be involved in other regulatory pathways. However, recent data suggest a role for IKK-alpha in NF-kappaB-dependent gene expression in response to cytokine treatment. Here we demonstrate nuclear accumulation of IKK-alpha after cytokine exposure, suggesting a nuclear function for this protein. Consistent with this, chromatin immunoprecipitation (ChIP) assays reveal that IKK-alpha was recruited to the promoter regions of NF-kappaB-regulated genes on stimulation with tumour-necrosis factor-alpha. Notably, NF-kappaB-regulated gene expression is suppressed by the loss of IKK-alpha and this correlates with a complete loss of gene-specific phosphorylation of histone H3 on serine 10, a modification previously associated with positive gene expression. Furthermore, we show that IKK-alpha can directly phosphorylate histone H3 in vitro, suggesting a new substrate for this kinase. We propose that IKK-alpha is an essential regulator of NF-kappaB-dependent gene expression through control of promoter-associated histone phosphorylation after cytokine exposure. These findings provide additional insight into the role of the IKK complex in NF-kappaB-regulated gene expression.

Animals↗
PubMed2005

The C. elegans histone deacetylase HDA-1 is required for cell migration and axon pathfinding.

Histone proteins play integral roles in chromatin structure and function. Histones are subject to several types of posttranslational modifications, including acetylation, which can produce transcriptional activation. The converse, histone deacetylation, is mediated by histone deacetylases (HDACs) and often is associated with transcriptional silencing. We identified a new mutation, cw2, in the Caenorhabditis elegans hda-1 gene, which encodes a histone deacetylase. Previous studies showed that a mutation in hda-1, e1795, or reduction of hda-1 RNA by RNAi causes defective vulval and gonadal development leading to sterility. The hda-1(cw2) mutation causes defective vulval development and reduced fertility, like hda-1(e1795), albeit with reduced severity. Unlike the previously reported hda-1 mutation, hda-1(cw2) mutants are viable as homozygotes, although many die as embryos or larvae, and are severely uncoordinated. Strikingly, in hda-1(cw2) mutants, axon pathfinding is defective; specific axons often appear to wander randomly or migrate in the wrong direction. In addition, the long range migrations of three neuron types and fasciculation of the ventral nerve cord are defective. Together, our studies define a new role for HDA-1 in nervous system development, and provide the first evidence for HDAC function in regulating neuronal axon guidance.

Amino Acid Sequence↗
PubMed2003

Mitogen-activated protein kinase modulation of nuclear factor-kappaB-induced granulocyte macrophage-colony-stimulating factor release from human alveolar macrophages.

Granulocyte macrophage-colony-stimulating factor (GM-CSF), released from alveolar macrophages (AM), is an important regulator of eosinophil, T cell, and macrophage function and survival. We determined the mechanisms of GM-CSF regulation in AM from normal volunteers activated by lipopolysaccharide (LPS) by examining the role of nuclear factor-kappaB (NF-kappaB), and of p38 mitogen-activated protein (MAP) kinase and MAP kinase kinase (MKK-1). PD 098059 (10 microM), an inhibitor of upstream activator of MKK-1, inhibited GM-CSF expression, but the expression of GM-CSF was not inhibited by SB 203580 (10 microM), an inhibitor of p38-MAP kinase. Phosphorylation of extracellular signal-regulated kinase-1 (ERK-1), ERK-2, and p38 MAP kinase by LPS were demonstrated on Western blot analysis. LPS increased NF-kappaB:DNA binding as examined by electrophoretic mobility shift assay, but this was not suppressed by PD 098059 or by SB 203580. LPS induced an increase in NF-kappaB activation as examined by p50 translocation assay without suppression by PD 098059 or by SB 203580. SN50 (100 microM), an inhibitor of NF-kappaB translocation and the specific IKK-2-Inhibitor (AS602868; 10 microM), also prevented GM-CSF expression and release induced by LPS, indicating that GM-CSF release is NF-kappaB-dependent. PD 098059, but not SB 203580, inhibited LPS-induced histone acetyltransferase (HAT) activity, indicating chromatin modification. Furthermore, AS602868 and SN 50 suppressed LPS-induced HAT activity. TSA (10 ng/ml), an inhibitor of histone deacetylase (HDAC), reversed the inhibitory effect of PD 098059, SB 203580, SN 50 and AS602868 on GM-CSF release. GM-CSF expression and release in AM is controlled by NF-kappaB activation, and this is modulated by phosphorylation of MKK-1 and p38 MAP kinase acting on histone acetylation.

Acetyltransferases↗
PubMed2004

Towards a unified and interdisciplinary model of ageing.

Researchers currently disagree about the appropriate biomarkers to monitor when measuring the ageing process. The major problem is identifying symptoms that are an end in and of themselves, from symptoms that are tied directly to the root cause, or causes, of ageing. This is most likely the reason that numerous, diverse and plausible theories for ageing co-exist. When young and old nuclei are exchanged between cells, the age of the resulting cell correlated with the nucleus. This suggests a large role of the nucleus as the target of ageing, although the sources of ageing may originate externally. There are three processes that occur when eukaryotes age. They are: (1) a progressive and patterned alteration of the structure of chromosomes after young adulthood has been reached, (2) a progressive and patterned malfunction of the degradation systems, and (3) age-altered post-translational modifications of proteins. A change in any one of these processes often causes a ripple effect that affects the other two processes. This paper begins by stating that the above three processes are the appropriate biomarkers of ageing. These three processes are coordinated with one another under normal physiological conditions. For example, proteasomes and their subunits have been found to regulate excision repair, transcription, and the turnover of nuclear/cytoplasmic receptors. The degradation system is also responsible for the removal of oxidized histones and other factors, which influence chromosome structure. Regulatory post-translational modifications at the histone level include methylation, phosphorylation, and acetylation. In addition, the above three processes undergo age related changes. Some of these modifications represent valid responses by the cell, but many do not. The effect of these age-altered macromolecules is perverse and unpredictable. For example, the cell's age-compromised degradation allows the accumulation of signaling complexes, which no longer match the needs of the cell. Age related histone and non-histone post-translational modifications alter both chromosome structure and expression. Nuclear pores have been found to slowly decrease in number in an age dependent manner. These pores have been found associated with the nuclear lamin. Several types of mutations in the lamin A gene cause progeria like symptoms. There is a diverse set of mechanisms that cause age related post-translational modifications. Previous attempts to find a commonality among those modifications have been disappointing. This paper will present a possible explanation that involves conformational changes caused by ionic and other perturbations in the nucleoplasm.

Adaptation, Physiological↗
PubMed2005

The kinase haspin is required for mitotic histone H3 Thr 3 phosphorylation and normal metaphase chromosome alignment.

Post-translational modifications of conserved N-terminal tail residues in histones regulate many aspects of chromosome activity. Thr 3 of histone H3 is highly conserved, but the significance of its phosphorylation is unclear, and the identity of the corresponding kinase unknown. Immunostaining with phospho-specific antibodies in mammalian cells reveals mitotic phosphorylation of H3 Thr 3 in prophase and its dephosphorylation during anaphase. Furthermore we find that haspin, a member of a distinctive group of protein kinases present in diverse eukaryotes, phosphorylates H3 at Thr 3 in vitro. Importantly, depletion of haspin by RNA interference reveals that this kinase is required for H3 Thr 3 phosphorylation in mitotic cells. In addition to its chromosomal association, haspin is found at the centrosomes and spindle during mitosis. Haspin RNA interference causes misalignment of metaphase chromosomes, and overexpression delays progression through early mitosis. This work reveals a new kinase involved in composing the histone code and adds haspin to the select group of kinases that integrate regulation of chromosome and spindle function during mitosis and meiosis.

Amino Acid Sequence↗
PubMed2004

[The relationship of DNA methylation and histone methylation].

In and out of the eukaryotic genomes, there exist many covalent modifications, of which are the methylation of DNA and histones, and they are both involved in genes silencing, in which the methylation of DNA and H3K9 are synergistic, but the methylation of H3K4 is antagonistic to them. The recent studies showed that these two methylations are correlated, that is, DNA methylation is dependent on the methylation of H3K9. However, the relationship of these two methylations is more complicated in mammals than in lower eukaryotons and plants.

Animals↗
PubMed2005

Clinical development of histone deacetylase inhibitors as anticancer agents.

Acetylation is a key posttranslational modification of many proteins responsible for regulating critical intracellular pathways. Although histones are the most thoroughly studied of acetylated protein substrates, histone acetyltransferases (HATs) and deacetylases (HDACs) are also responsible for modifying the activity of diverse types of nonhistone proteins, including transcription factors and signal transduction mediators. HDACs have emerged as uncredentialed molecular targets for the development of enzymatic inhibitors to treat human cancer, and six structurally distinct drug classes have been identified with in vivo bioavailability and intracellular capability to inhibit many of the known mammalian members representing the two general types of NAD+-independent yeast HDACs, Rpd3 (HDACs 1, 2, 3, 8) and Hda1 (HDACs 4, 5, 6, 7, 9a, 9b, 10). Initial clinical trials indicate that HDAC inhibitors from several different structural classes are very well tolerated and exhibit clinical activity against a variety of human malignancies; however, the molecular basis for their anticancer selectivity remains largely unknown. HDAC inhibitors have also shown preclinical promise when combined with other therapeutic agents, and innovative drug delivery strategies, including liposome encapsulation, may further enhance their clinical development and anticancer potential. An improved understanding of the mechanistic role of specific HDACs in human tumorigenesis, as well as the identification of more specific HDAC inhibitors, will likely accelerate the clinical development and broaden the future scope and utility of HDAC inhibitors for cancer treatment.

Animals↗
PubMed1993

Chromatin transitions during early Xenopus embryogenesis: changes in histone H4 acetylation and in linker histone type.

We describe major transitions in the type and modification of chromatin-associated proteins during the early development of Xenopus laevis. Histone H4 is stored in the diacetylated form in the egg and is progressively deacetylated during normal development. If histone deacetylases are inhibited with sodium butyrate, hyperacetylated histone H4 only accumulates after the mid-blastula transition. The type of linker histone in chromatin also changes during embryogenesis, from predominantly the B4 protein at the mid-blastula transition to predominantly histone H1 at the end of gastrulation. These transitions in chromatin composition correlate with major changes in the replicative and transcriptional activity of embryonic nuclei.

Acetylation↗
PubMed1975

Studies on highly metabolically active acetylation and phosphorylation of histones.

The capacity to effectively label tumor cell hostones using very short pulses of [3-H]acetate and [32-P]phosphate (1 to 10 min) has been developed. Four histone fractions F3, F2a1, F2a2, and F2b are extensively acetylated in short time periods. About 70% of the acetate accumulated on the histone during a short pulse is removed with a half-life of similar to 3 min. The rest of the metabolically active acetate is removed with a half-life of 30 to 40 min. Histones F2a1, F2a2, and F1 are acetylated at the NH2 terminus and this modification is metabolically stable. In short pulses, histones are labeled with 32-P in the order F2a2 greater than F1 greater than F3 greater than F2a1 greater than F2b. All fractions have a fairly rapid turnover time (t1/2 similar 20 to 40 min) except F1 phosphate which turns over some 5 times more slowly.

Acetates↗
PubMed2005

The role of mammalian DNA methyltransferases in the regulation of gene expression.

The term epigenetic modification denotes reversible traits of gene expression that do not include alterations to the DNA sequence. These epigenetic alterations are responsible for chromatin structure stability, genome integrity, modulation of tissue-specific gene expression, embryonic development, genomic imprinting and X-chromosome inactivation in females. Epigenetic changes include reversible DNA methylation and histone acetylation or methylation. The modification of mammalian genomic DNA includes the methylation at the 5-position of the cytosine (C) residue within cytosine-guanine dinucleotides (CpG), resulting in the formation of 5-methylcytosine (m5C). Regulatory DNA sequences in vertebrates often have little or no methylation. The methylation of mammalian genomic DNA is catalyzed by DNA methyltransferases (DNMTs), which play a special role in the initiation of chromatin remodeling and gene expression regulation. The mammalian DNMTs are DNMT1, DNMT3A and DNMT3B, which together with accessory proteins, like DNMT3L, are responsible for methylation pattern acquisition during gametogenesis, embryogenesis and somatic tissue development. Reversible epigenetic alterations lead to selective utilization of genome information through the activation or inactivation of transcription of functional genes during gametogenesis, embryogenesis and cell differentiation. Recently, several disparate isoforms of DNMT1 were identified in human somatic and female and male germ cells. Recent advances in the investigation of DNMT function in epigenetic DNA changes have formed the basis of the understanding of various disorder etiopathogeneses, and as a result, have facilitated and enabled new therapies with respect to these diseases.

Animals↗
PubMed2005

Methylation of histones: playing memory with DNA.

Nucleosomal histones can be methylated in vivo at multiple residues and defined methylation patterns are related to distinct functional readouts of chromosomal DNA. Histone methylation has emerged as an important post-translational modification involved in transcriptional regulation and genome integrity. Recent progress in determining the cis and trans determinants of this process revealed multiple roles for histone methylation in epigenetic memory of active and silent states. The analysis of imprinted, X-linked and heterochromatic sequences disclosed mechanistic similarities for heritable transcriptional repression, pointing to a common mode of action. Moreover, the view of histone methylation as a stable modification has recently been challenged by studies revealing a number of pathways that are capable of removing histone methylation. Thus, in addition to having great in vivo complexity, this modification appears more dynamic then was previously thought.

Animals↗
PubMed1988

Binding of high-mobility-group proteins HMG 14 and HMG 17 to DNA and histone H1 as influenced by phosphorylation.

We have used affinity chromatography to study the effects of phosphorylation of calf thymus high-mobility-group proteins HMG 14 and HMG 17 on their binding properties towards calf thymus single- and double-stranded DNA and histone H1. Without in vitro phosphorylation, HMG 14 and HMG 17 eluted from double-stranded DNA-columns at 200 mM NaCl. HMG 14 was released from single-stranded DNA-column at 300 mM NaCl and from H1-column at 130 mM NaCl, whereas the corresponding values for HMG 17 were 230 mM and 20 mM, respectively. Phosphorylation of HMG 14 and HMG 17 by cAMP-dependent protein kinase (A-kinase) decreased markedly their affinity (270 mM and 200 mM NaCl, respectively) for single-stranded DNA, whereas HMG 14 phosphorylated by nuclear protein kinase II (NII-kinase) eluted only slightly (290 mM NaCl) ahead of the unphosphorylated protein. HMG 14 phosphorylated by both A-kinase and NII-kinase eluted from double-stranded DNA-columns almost identically (190 mM NaCl) with the unphosphorylated protein. Interestingly, phosphorylation of HMG 14 by NII-kinase increased considerably its affinity for histone H1 and the phosphorylated protein eluted at 200 mM NaCl. Phosphorylation of HMG 14 by A-kinase did not alter its interaction towards histone H1. These results indicate that modification of HMG 14 by phosphorylation at specific sites may have profound effects on its binding properties towards DNA and histone H1, and that HMG 17 has much weaker affinity for single-stranded DNA and histone H1 than HMG 14.

Animals↗
PubMed1998

Nucleosomal DNA regulates the core-histone-binding subunit of the human Hat1 acetyltransferase.

BACKGROUND: In eukaryotic cells, newly synthesized histone H4 is acetylated at lysines 5 and 12, a transient modification erased by deacetylases shortly after deposition of histones into chromosomes. Genetic studies in Saccharomyces cerevisiae revealed that acetylation of newly synthesized histones H3 and H4 is likely to be important for maintaining cell viability; the precise biochemical function of this acetylation is not known, however. The identification of enzymes mediating site-specific acetylation of H4 at Lys5 and Lys12 may help explain the function of the acetylation of newly synthesized histones. RESULTS: A cDNA encoding the catalytic subunit of the human Hat1 acetyltransferase was cloned and, using specific antibodies, the Hat1 holoenzyme was purified from human 293 cells. The human enzyme acetylates soluble but not nucleosomal H4 at Lys5 and Lys12 and acetylates histone H2A at Lys5. Unexpectedly, we found Hat1 in the nucleus of S-phase cells. Like its yeast counterpart, the human holoenzyme consists of two subunits: a catalytic subunit, Hat1, and a subunit that binds core histones, p46, which greatly stimulates the acetyltransferase activity of Hat1. Both p46 and the highly related p48 polypeptide (the small subunit of human chromatin assembly factor 1; CAF-1) bind directly to helix 1 of histone H4, a region that is not accessible when H4 is in chromatin. CONCLUSIONS: We suggest that p46 and p48 are core-histone-binding subunits that target chromatin assembly factors, chromatin remodeling factors, histone acetyltransferases and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA.

Acetylation↗
PubMed1988

Differential acetylation of core histones in rat cerebral cortex neurons during development and aging.

Core histones can be modified by aceylation and this modification has been correlated with the modulation of chromatin condensation and histone deposition. We have now studied the levels of acetylation of the core histones in rat brain cortical neurons from the middle of the period of neuronal proliferation through postnatal development and aging. The results show that the level of acetylation of H4 decreases with age. The kinetics of H4 deacetylation show a perinatal fast phase followed by a much slower phase that spans the rest of the period examined. H4 deacetylation is accounted for by the decrease of the monoacetylated species, the proportions of the more highly acetylated species remaining essentially constant. By contrast to histone H4, the overall levels of acetylation and the proportions of the different acetylated species of H2A, H2B and H3 remain unchanged throughout the period examined. Furthermore, the variants belonging to a given histone class always show the same level of acetylation. The fact that in neurons the level of monoacetylated H4 decreases during development and aging, in sharp contrast with the constancy of the levels of all other acetylated histone species, raises the possibility that in interphase chromatin monoacetylated H4 may have a central role in the modulation of chromatin structure. The results also suggest that the slow decrease of the proportion of monoacetylated H4 may imply a gradual loss of chromatin structural plasticity and thus lead to aging.

Acetylation↗