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PubMedDate not supplied

H2AX: the histone guardian of the genome.

At close hand to one's genomic material are the histones that make up the nucleosome. Standing guard, one variant stays hidden doubling as one of the core histones. But, thanks to its prime positioning, a variation in the tail of H2AX enables rapid modification of the histone code in response to DNA damage. A role for H2AX phosphorylation has been demonstrated in DNA repair, cell cycle checkpoints, regulated gene recombination events, and tumor suppression. In this review, we summarize what we have learned about this marker of DNA breaks, and highlight some of the questions that remain to be elucidated about the physiological role of H2AX. We also suggest a model in which chromatin restructuring mediated by H2AX phosphorylation serves to concentrate DNA repair/signaling factors and/or tether DNA ends together, which could explain the pleotropic phenotypes observed in its absence.

Animals↗
PubMed2005

Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes.

Despite advances in understanding the role of histone deacetylases (HDACs) in tumorigenesis, the mechanism by which HDAC inhibitors mediate antineoplastic effects remains elusive. Modifications of the histone code alone are not sufficient to account for the antitumor effect of HDAC inhibitors. The present study demonstrates a novel histone acetylation-independent mechanism by which HDAC inhibitors cause Akt dephosphorylation in U87MG glioblastoma and PC-3 prostate cancer cells by disrupting HDAC-protein phosphatase 1 (PP1) complexes. Of four HDAC inhibitors examined, trichostatin A (TSA) and HDAC42 exhibit the highest activity in down-regulating phospho-Akt, followed by suberoylanilide hydroxamic acid, whereas MS-275 shows only a marginal effect at 5 microm. This differential potency parallels the respective activities in inducing tubulin acetylation, a non-histone substrate for HDAC6. Evidence indicates that this Akt dephosphorylation is not mediated through deactivation of upstream kinases or activation of downstream phosphatases. However, the effect of TSA on phospho-Akt can be rescued by PP1 inhibition but not that of protein phosphatase 2A. Immunochemical analyses reveal that TSA blocks specific interactions of PP1 with HDACs 1 and 6, resulting in increased PP1-Akt association. Moreover, we used isozyme-specific small interfering RNAs to confirm the role of HDACs 1 and 6 as key mediators in facilitating Akt dephosphorylation. The selective action of HDAC inhibitors on HDAC-PP1 complexes represents the first example of modulating specific PP1 interactions by small molecule agents. From a clinical perspective, identification of this PP1-facilitated dephosphorylation mechanism underscores the potential use of HDAC inhibitors in lowering the apoptosis threshold for other therapeutic agents through Akt down-regulation.

Apoptosis↗
PubMed1990

Genetic analysis of histone H4: essential role of lysines subject to reversible acetylation.

The nucleosome is the fundamental unit of assembly of the chromosome and reversible modifications of the histones have been suggested to be important in many aspects of nucleosome function. The structure-function relations of the amino-terminal domain of yeast histone H4 were examined by the creation of directed point mutations. The four lysines subject to reversible acetylation were essential for histone function as the substitution of arginine or asparagine at these four positions was lethal. No single lysine residue was completely essential since arginine substitutions at each position were viable, although several of these mutants were slower in completing DNA replication. The simultaneous substitution of glutamine for the four lysine residues was viable but conferred several phenotypes including mating sterility, slow progression through the G2/M period of the division cycle, and temperature-sensitive growth, as well as a prolonged period of DNA replication. These results provide genetic proof for the roles of the H4 amino-terminal domain lysines in gene expression, replication, and nuclear division.

Acetylation↗
PubMed2004

4-Hydroxynonenal oxidatively modifies histones: implications for Alzheimer's disease.

There is increasing evidence of DNA oxidation and altered DNA repair mechanisms in Alzheimer's disease (AD) brain. Histones, which interact with DNA, conceivably could provide a protective shield for DNA against oxidative stress. However, because of their abundant lysine residues, histones may be a target for 4-hydroxynonenal (HNE) modification. In this study, we have shown that HNE binds to histones and that this binding affects the conformation of the histone, measured by electron paramagnetic resonance in conjunction with a protein-specific spin label. The covalent modification to the histone by HNE affects the ability of the histone to bind DNA. Interestingly, acetylated histones appear to be more susceptible to HNE modifications than control histones. Conceivably, altered DNA-histone interactions, subsequent to oxidative modification of histones by the lipid peroxidation product HNE, may contribute to the vulnerability of DNA to oxidation in AD brain.

Acetylation↗
PubMed2004

Histone deacetylase inhibitors.

The base sequence of DNA provides the genetic code for proteins. The regulation of expression or suppression of gene transcription is largely determined by the structure of the chromatin--referred to as epigenetic gene regulation (Agalioti et al., 2002; Jenuwein and Allis, 2001; Richards and Elgin, 2002; Spotswood and Turner, 2002; Zhang and Reinberg, 2001). Posttranslational modifications of the histones of chromatin play an important role in regulating gene expression. Some of the most extensively studied epigenetic modifications involve acetylation/deacetylation of lysines in the tails of the core histones, which is controlled by the action of histone deacetylases (HDACs) and histone acetyltransferases (HATs). A controlled balance between histone acetylation and deacetylation appears to be essential for normal cell growth (Waterborg, 2002). Alterations in the structure or expression of HATs and HDACs occur in many cancers (Jones and Baylin, 2002; Marks et al., 2001, 2003; Timmermann et al., 2001; Wang et al., 2001). A structurally diverse group of molecules has been developed that can inhibit HDACs (HDACi) (Arts et al., 2003; Bouchain and Delorme, 2003; Curtin and Glaser, 2003; Johnstone and Licht, 2003; Marks et al., 2003; Remiszewski, 2003; Richon et al., 1998; Yoshida et al., 2003). These inhibitors induce growth arrest, differentiation, and?or apoptosis of cancer cells in vitro and in in vivo tumor-bearing animal models. Clinical trials with several of these agents have shown that certain HDACi have antitumor activity against various cancers at doses that are well tolerated by patients (Gottlicher et al., 2001; Kelly et al., 2002a,b; Piekarz et al., 2001; Wozniak et al., 1999).

Acetylation↗
PubMed1988

Histone accessibility determined by lysine-specific acetylation in chicken erythrocyte nuclei.

N-Hydroxysulfosuccinimidyl [3H]acetate was synthesized and, following the determination of the optimal reaction conditions, was used to acetylate histones in chicken erythrocyte nuclei at 4 degrees C, pH 8. The histones were extracted from the labelled nuclei and the distribution of the acetyl groups determined from the amount of tritiated acetate in isolated peptides. The relative degree of acetylation of molecules was H1 1.0, H5 0.81, H2B 0.48, H2A 0.24, H3 0.24, H4 0.16. Histone H1 is the most exposed histone followed by H5. The core histones are much less accessible to chemical modification than the linker histones by a factor of 4-5. Histones H2A, H2B and H5 appear to be labelled at random along the entire polypeptide chain, while histones H3 and H4 are labelled almost exclusively in the first 30 residues from the N terminus. Control and acetylated chicken erythrocyte nuclei were digested with DNase I and the resulting DNA hybridized to globin and ovalbumin cDNAs. Acetylation, at 14 molecules acetate/core nucleosome or 20 molecules acetate/chromatosome, increased the DNase I sensitivity of the ovalbumin gene to that of the globin sequences in the control sample, while the globin sequences became even more nuclease-sensitive. Our results suggest that increased sensitivity of chromatin towards nuclease digestion might be due to increased solubility of the chromatin fibre.

Acetylation↗
PubMed2004

Structure and function of histone methyltransferases.

Histones are the major protein constituent of chromatin in the eukaryotic nucleus. These proteins undergo a host of different post-translational modifications, including phosphorylation, acetylation, and methylation, which have profound effects on the remodeling of chromatin. Histone modifications can function either individually or combinatorially to govern such processes as transcription, replication, DNA repair, and apoptosis. Recent studies have focused on histone arginine and lysine methylation and the roles of these modifications in transcriptional regulation and the establishment of heterochromatin. Concomitantly, several families of histone methyltransferases (HMTs) have been identified that catalyze the methylation of specific arginines or lysines in histones H3 and H4. Not surprisingly, many of these methyltransferase genes had been previously identified as important genetic regulators in organisms such as yeast and Drosophila, which underscores the importance of histone methylation in transcriptional control and chromatin remodeling. Structures of several representatives of these HMT families have recently been determined, yielding insight into their catalytic mechanism and histone substrate specificity. The focus of this review is to briefly summarize the roles of histone methylation in chromatin remodeling and to discuss the structures, substrate specificities, and mechanisms of the different classes of HMTs.

Animals↗
PubMed1983

Immunoaffinity fractionation of the poly(ADP-ribosyl)ated domains of chromatin.

Antibody to poly(ADP-ribose) has been covalently coupled to Sepharose and utilized to isolate selectively oligonucleosomes undergoing the poly(ADP-ribosyl)ation reaction from the bulk of chromatin. Approximately 12% of the unfractionated oligonucleosomes were bound to the immunoaffinity column and these represented essentially 100% of the original poly(ADP-ribosyl)ated nucleosomal species in the unfractionated chromatin. Poly(ADP-ribosyl)ated chromatin was not bound by preimmune IgG columns. KSCN eluted the modified nucleosomes in the form of nucleoprotein complexes. The eluted chromatin components were shown to contain poly(ADP-ribosyl)ated histones as well as automodified poly(ADP-ribose) polymerase. By using [3H]lysine- and [3H]arginine-labeled chromatin, it was shown that the poly-(ADP-ribosyl)ated histones, attached to stretches of oligonucleosomes bound to the column, had a 6-fold enrichment of the modification compared to histones of the unfractionated chromatin. This indicated that non-poly(ADP-ribosyl)ated nucleosomes, connected and proximal to the modified regions, were copurified by this procedure. This allowed characterization of the oligonucleosomal DNA around poly(ADP-ribosyl)ated chromatin domains to be compared with the unbound bulk chromatin. The data indicated that immunofractionated poly(ADP-ribosyl)ated oligonucleosomal DNA contained significant amounts of internal single-strand breaks compared with bulk chromatin. The bound nucleo-protein complexes were found to be enzymatically active for poly(ADP-ribose) polymerase after elution from the antibody column. In contrast, the unbound nucleosomes, representing 90% of the unfractionated chromatin, were totally inactive in the poly(ADP-ribosyl)ation reaction.

Chromatin↗
PubMed2005

The nuclear-envelope protein and transcriptional repressor LAP2beta interacts with HDAC3 at the nuclear periphery, and induces histone H4 deacetylation.

Nuclear-envelope proteins have been implicated in diverse and fundamental cell functions, among them transcriptional regulation. Gene expression at the territory of the nuclear periphery is known to be repressed by epigenetic modifications such as histone deacetylation and methylation. However, the mechanism by which nuclear-envelope proteins are involved in such modifications is still obscure. We have previously shown that LAP2beta, an integral nuclear-envelope protein that contains the chromatin-binding LEM domain, was able to repress the transcriptional activity of the E2F5-DP3 heterodimer. Here, we show that LAP2beta's repressive activity is more general, encompassing various E2F members as well as other transcription factors such as p53 and NF-kappaB. We further show that LAP2beta interacts at the nuclear envelope with HDAC3, a class-I histone deacetylase, and that TSA (an HDAC inhibitor) abrogates LAP2beta's repressive activity. Finally, we show that LAP2beta is capable of inducing histone-H4 deacetylation. Our data provide evidence for the existence of a previously unknown repressive complex, composed of an integral nuclear membrane protein and a histone modifier, at the nuclear periphery.

Cell Line, Tumor↗
PubMed2006

Histone citrullination by protein arginine deiminase: is arginine methylation a green light or a roadblock?

Protein citrullination, a once-obscure post-translational modification (PTM) of peptidylarginine, has recently become an area of significant interest because of its suspected role in human disease states, including rheumatoid arthritis and multiple sclerosis, and also because of its newfound role in gene regulation. One protein isozyme responsible for this modification, protein arginine deiminase 4 (PAD4), has also been proposed to "reverse" epigenetic histone modifications made by the protein arginine methyltransferases. Here, we review the in vivo and in vitro studies of transcriptional regulation by PAD4, evaluate conflicting evidence for its ability to use methylated peptidylarginine as a substrate, and highlight promising areas of future work. Understanding the interplay of multiple arginine PTMs is an emerging area of importance in health and disease and is a topic best addressed by novel tools in proteomics and chemical biology.

Arginine↗
PubMed1986

Increased acetylation of histones at an early stage of oestradiol-mediated gene activation in the liver of immature chicks.

The vitellogenin system of chicken was used to examine alterations in the microheterogeneity of chromosomal proteins in the course of steroid hormone-mediated gene expression. After administration of oestradiol-17 beta there is a dramatic increase in the number of copies of vitellogenin m-RNA in the liver of male oviparous animals, like Xenopus and chicken. According to earlier reports the rapid increase in transcriptional activity starts after a lag of 4 h. The system has also been examined as to the number of DNase I hypersensitive sites which appear to correlate with the degree of differentiation and hormonal activation. The time course of [3H]acetate incorporation into the histone fraction was monitored and the microheterogeneity of histones analysed by acid-Triton-urea gel electrophoresis. The results show that there is an increased degree of acetylation of histones in the liver of immature chicks as a result of oestradiol-17 beta administration. The change in the modification pattern of histones was found to be an early event, correlated with the time course of appearance of new DNase I hypersensitive sites and the onset of vitellogenin m-RNA synthesis. These observations are in agreement with an earlier report about the increase in the acetylation of histones in fetal guinea pig uterus after oestradiol treatment [1]. The results suggest that the acetylation of histones might be a prerequisite for the removal of structures for efficient gene repression and the establishment of DNase I hypersensitive sites.

Acetylation↗
PubMed1994

Ca(2+)-calmodulin-dependent phosphorylation of arginine in histone 3 by a nuclear kinase from mouse leukemia cells.

A Ca(2+)-calmodulin dependent histone 3 kinase was partially purified from a low salt (150 mM NaCl) nuclear extract of mouse leukemia cells by calmodulin-Sepharose affinity chromatography. In vitro, the kinase activity transferred gamma-phosphate from ATP to histone 3 to form an acid-labile and alkaline-stable linkage. Under the assay conditions 1.8 mol of phosphate are incorporated per mol of histone 3. Upon modification of arginine residues with phenylglyoxal prior to phosphorylation, a considerable decrease in the amount of phosphate transferred to histone 3 was observed. Amino acid analysis revealed that H3 was phosphorylated on arginine residues. To identify the phosphorylated peptide(s), histone 3 was cleaved with cyanogen bromide prior to phosphorylation. The phosphorylated mixture was then separated by gel filtration high-performance liquid chromatography under denaturing conditions. Fragments I (N-terminal 10.3-kDa peptide) and III (C-terminal 1.7-kDa peptide) were both phosphorylated. Amino acid sequencing further revealed that the molar yields of 3 of the 4 arginines present in the phosphorylated cyanogen bromide fragment III were reduced by a factor of about 10 compared with the corresponding arginines from the unphosphorylated fragment. In the case of fragment I, 25 cycles of Edman degradation revealed that the recovery of only arginine 2 was reduced by a factor of 20. The putative phosphorylation sites are arginines 2, 128, 129, and 131. The sequence information offered an indirect evidence that these arginines were the sites of phosphorylation. The kinase described in this report represents a first member of a potentially important new class of kinases which are Ca(2+)-calmodulin dependent and which phosphorylate arginine.

Amino Acid Sequence↗
PubMed2004

Role of protein methylation in regulation of transcription.

In the last few years, the discovery of lysine and arginine methylation in histones and other proteins and the enzymes that carry out these posttranslational modifications has added a new dimension to the signal transduction field. In particular, there has been a huge surge in our understanding of how methylation of nucleosomal histones at specific lysine or arginine residues affects chromatin conformations and either facilitates or inhibits transcription from neighboring genes. It appears that the responsible methyltransferases can be targeted in some cases to specific genes and in other cases to broader regions of euchromatin or heterochromatin. Methylation of histones is mechanistically linked to other types of histone modifications, such as acetylation, phosphorylation, and monoubiquitylation; combinations of these modifications cooperate to regulate chromatin structure and transcription by stimulating or inhibiting binding of specific proteins. Although lysine methylation has thus far been observed almost exclusively on histones, arginine methylation has been observed on a variety of other proteins associated with gene regulation, including DNA-binding transcriptional activators, transcriptional coactivators, and many RNA binding proteins involved in RNA processing, transport, and stability. Thus, lysine and arginine methylation of proteins, like many other types of posttranslational modifications, are regulated steps of many specific signaling pathways.

Amino Acid Sequence↗
PubMed2005

The role of histone H2Av variant replacement and histone H4 acetylation in the establishment of Drosophila heterochromatin.

Activation and repression of transcription in eukaryotes involve changes in the chromatin fiber that can be accomplished by covalent modification of the histone tails or the replacement of the canonical histones with other variants. Here we show that the histone H2A variant of Drosophila melanogaster, H2Av, localizes to the centromeric heterochromatin, and it is recruited to an ectopic heterochromatin site formed by a transgene array. His2Av behaves genetically as a PcG gene and mutations in His2Av suppress position effect variegation (PEV), suggesting that this histone variant is required for euchromatic silencing and heterochromatin formation. His2Av mutants show reduced acetylation of histone H4 at Lys 12, decreased methylation of histone H3 at Lys 9, and a reduction in HP1 recruitment to the centromeric region. H2Av accumulation or histone H4 Lys 12 acetylation is not affected by mutations in Su(var)3-9 or Su(var)2-5. The results suggest an ordered cascade of events leading to the establishment of heterochromatin and requiring the recruitment of the histone H2Av variant followed by H4 Lys 12 acetylation as necessary steps before H3 Lys 9 methylation and HP1 recruitment can take place.

Acetylation↗
PubMed1981

Comparison of the interaction of cyclic nucleotide-dependent protein kinases with mononucleosomes and free histones.

Arginine-rich histones H2A, H2B, H3 and H4 contain two regions of interaction with cyclic nucleotide-dependent protein kinases: a substrate phosphorylation site and a region which noncompetitively inhibits cyclic nucleotide binding to the protein kinases. We have compared the interaction of cyclic nucleotide-dependent protein kinases with these two sites in histones which are organized in nucleosome structures with the interaction of the enzymes with free histones. Whereas histones in solution are readily phosphorylated by cyclic GMP-dependent protein kinase and the catalytic subunit of cyclic AMP-dependent protein kinase, mononucleosomes are not phosphorylated by these enzymes. Histones extracted from mononucleosomes can be phosphorylated, indicating that the lack of phosphorylation of nucleosomes is not due to covalent modification of the histones but to their organization within the nucleosome structure. Whereas histones in solution are effective noncompetitive inhibitors of cyclic GMP binding to cyclic GMP-dependent protein kinase and of cyclic AMP binding to the regulatory subunits of cyclic AMP-dependent protein kinase, mononucleosomes do not affect cyclic nucleotide binding. These studies indicate that histones which are organized in nucleosome structures are neither substrates nor modifiers of cyclic nucleotide-dependent protein kinases.

Animals↗
PubMed2000

The drosophila MSL complex acetylates histone H4 at lysine 16, a chromatin modification linked to dosage compensation.

In Drosophila, dosage compensation-the equalization of most X-linked gene products in males and females-is achieved by a twofold enhancement of the level of transcription of the X chromosome in males relative to each X chromosome in females. A complex consisting of at least five gene products preferentially binds the X chromosome at numerous sites in males and results in a significant increase in the presence of a specific histone isoform, histone 4 acetylated at lysine 16. Recently, RNA transcripts (roX1 and roX2) encoded by two different genes have also been found associated with the X chromosome in males. We have partially purified a complex containing MSL1, -2, and -3, MOF, MLE, and roX2 RNA and demonstrated that it exclusively acetylates H4 at lysine 16 on nucleosomal substrates. These results demonstrate that the MSL complex is responsible for the specific chromatin modification characteristic of the X chromosome in Drosophila males.

Animals↗
PubMed2026

Integrated histone and proteome analyses reveal convergent and distinct hepatotoxic mechanisms of tenuazonic acid and deoxynivalenol.

Mycotoxins are widespread dietary contaminants whose health impacts are expected to intensify under climate change. Although their mechanisms of toxicity remain incompletely understood, epigenetic dysregulation has been increasingly implicated. Here, mass spectrometry-based multi-omics was used to profile histone post-translational modifications and proteome dynamics in HepG2 cells exposed to seven mycotoxin conditions. Time-resolved analyses identified tenuazonic acid as the dominant cellular disruptor, inducing alterations in H3K27 and H1 variants, and revealing a previously unrecognized oxidative modification of the H1.0 N-terminal methionine (H1.0N-term0AcM0Ox) that retains the protein's N-terminal acetylation. An Alternaria toxin mixture induced similar H1 responses, largely driven by tenuazonic acid, while deoxynivalenol produced convergent chromatin and proteomic alterations. Proteomic remodeling was characterized by increased protein translation, reduced mitochondrial complex IV expression, and impaired cholesterol biosynthesis, whereas sterigmatocystin activated DNA replication and repair pathways. Together, these findings demonstrate that mycotoxins disrupt chromatin organization, protein synthesis, and lipid metabolism, providing toxicological insight into hepatocellular dysfunction. These findings warrant further validation and mechanistic investigation in future hypothesis-driven studies of mycotoxin exposure.

Trichothecenes↗