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PubMed1983

Synthesis of yeast histone 3 in an Escherichia coli cell-free system.

The gene for histone H3 from the yeast Saccharomyces cerevisiae was placed under the control of the lac promoter of Escherichia coli by fusing the H3 coding sequence to that of beta-galactosidase. The gene was shown to be transcribed in vivo, but its product was not detected in cell extracts. However, synthesis of the fused polypeptide was detected in an in vitro transcription-translation system derived from E. coli. Proteolytic degradation of the newly synthesized polypeptides may be the cause of their apparent absence in the in vivo experiment.

Amino Acid Sequence↗
PubMed1997

Differential expression of the murine histone genes H3.3A and H3.3B.

The histone family of proteins is subdivided into two major groups: the main type histones, which are synthesized in coordination with DNA replication during the S-phase of the cell cycle, and the replacement histones, which can be synthesized in the absence of DNA replication substituting main type histone isoforms. Accumulation of replacement histone variants has been observed in several terminally differentiated tissues that have stopped cell division. The replacement subtype of the H3 class is termed H3.3. This protein is encoded by two different genes (H3.3A and H3.3B) that both code for the same amino acid sequence, but differ in nucleotide sequences and gene organization. This has been shown for human and avian H3.3A and H3.3B genes and for a murine H3.3B cDNA. In an attempt to define patterns of replacement histone H3.3 gene expression during male germ cell differentiation, we have constructed mouse testicular cDNA libraries and have isolated cDNAs corresponding to the murine H3.3A and H3.3B genes. Using probes specific for these two different genes we show by RNase protection analysis and by nonradioactive in situ hybridization with testis sections that H3.3A mRNA is present in pre- and postmeiotic cells, whereas expression of the H3.3B gene is essentially restricted to cells of the meiotic prophase.

Amino Acid Sequence↗
PubMed2000

Origin and persistence of the mitochondrial genome.

The mitochondrial genome comprises a circular, histone-free 'chromosome' of 16.6 kb of DNA, present in one or more copies in every mitochondrion. This chromosome has been tightly conserved for more than half a billion years, coding in every multicellular animal so far investigated, both vertebrate and invertebrate: (i) the same 13 protein subunits required for oxidative phosphorylation; (ii) a component of each of the two mitochondrial ribosome subunits; and (iii) the 22 transport RNAs present within the mitochondrion. Exons on the circle are tightly packed, with no spacing introns. Mitochondrial DNA is histone-free, has limited repair ability, and has a relatively high mutation-fixation rate. Inheritance is cytoplasmic and maternal, with epidemiological evidence (namely the familial distribution of polymorphisms) indicating that recombination with mtDNA of paternal origin is exceedingly rare. Thus the maintenance and evolution of mtDNA (its remarkably successful symbiotic persistence with the nuclear genome) has been essentially asexual. The machinery for homologous recombination is present in mitochondria of at least some species, however, and it might be surprising if it did not occur between circles in some circumstances. By bringing together the fields of mitochondrial biochemistry, evolutionary genetics, reproductive physiology, and neuromuscular medicine in focusing on the inheritance of normal and abnormal human mtDNA, we can hope to better understand the forces behind this genome's inheritance and what might be required of ovarian function to satisfy its accurate persistence over millions of years. Clinically we can hope also for a better understanding of ooplasmic factors in human fertility and in the wide manifestations of mitochondrial genomic disease.

Animals↗
PubMed2003

Modelling study on the protective role of OH radical scavengers and DNA higher-order structures in induction of single- and double-strand break by gamma-radiation.

PURPOSE: To quantify the protective effects of (non-histonic) OH-radical scavengers and DNA higher-order structures in induction of single- (ssbs) and double-strand breaks (dsbs) by gamma-rays. MATERIALS AND METHODS: Spatial distributions of energy depositions by gamma-rays in liquid water were modelled with the track structure modules of the biophysical simulation code PARTRAC. Such distributions were superimposed on different DNA structure models (e.g. linear DNA, SV40 'minichromosomes' and compact chromatin), and direct energy depositions in the sugar-phosphate were considered as potential (direct) ssbs. The diffusion and interaction of the main chemical species produced in liquid water radiolysis were explicitly simulated, and reactions of *OH with the sugar-phosphate were considered as potential (indirect) ssbs. Two ssb on opposite DNA strands within 10 base pairs were considered as one dsb. Yields of ssb and dsb Gy(-1) Dalton(-1) in different DNA target structures were calculated as a function of the *OH mean lifetime, whose inverse value was taken as representative of the scavenging capacity of the DNA environment. RESULTS AND CONCLUSIONS: A further validation of the models implemented in the PARTRAC code has been provided, thus allowing a better understanding of the mechanisms underlying DNA damage. More specifically, the protection due to *OH scavengers was separately quantified with respect to that due to histones and chromatin folding, which could be 'switched off' in the simulations. As expected, for a given value of the environment scavenging capacity, linear DNA was more susceptible to strand breakage than SV40 minichromosomes, which in turn showed higher damage yields with respect to cellular DNA due to the larger accessibility offered to *OH. Furthermore, by increasing the scavenging capacity, the break yields decreased in all structures and tended to coincide with direct damage yields. Very good agreement was found with available experimental data. Comparisons with data on 'nucleoid' DNA (i.e. unfolded and histone-depleted DNA) also suggested that the experimental procedures used to obtain such structures might lower the environment scavenging capacity owing to the loss of cellular scavengers.

DNA↗
PubMed2001

Yeast chromatin structure and regulation of GAL gene expression.

Yeast genomic DNA is covered by nucleosome cores spaced by short, discrete length linkers. The short linkers, reinforced by novel histone properties, create a number of unique and dynamic nucleosome structural features in vivo: permanent unpeeling of DNA from the ends of the core, an inability to bind even full 147 bp core DNA lengths, and facility to undergo a conformational transition that resembles the changes found in active chromatin. These features probably explain how yeast can maintain most of its genome in a transcribable state and avoid large-scale packaging away of inactive genes. The GAL genes provide a closely regulated system in which to study gene-specific chromatin structure. GAL structural genes are inactive without galactose but are highly transcribed in its presence; the expression patterns of the regulatory genes can account for many of the features of GAL structural gene control. In the inactive state, GAL genes demonstrate a characteristic promoter chromosomal organization; the major upstream activation sequence (UASG) elements lie in open, hypersensitive regions, whereas the TATA and transcription start sites are in nucleosomes. This organization helps implement gene regulation in this state and may benefit the organism. Induction of GAL expression triggers Gal4p-dependent upstream nucleosome disruption. Disruption is transient and can readily be reversed by a Gal80p-dependent nucleosome deposition process. Both are sensitive to the metabolic state of the cell. Induction triggers different kinds of nucleosome changes on the coding sequences, perhaps reflecting the differing roles of nucleosomes on coding versus promoter regions. GAL gene activation is a complex process involving multiple Gal4p activities, numerous positive and negative cofactors, and the histone tails. DNA bending and chromosomal architecture of the promoter regions may also play a role in GAL regulation. Regulator-mediated competition between nucleosomes and the TATA binding protein complex for the TATA region is probably a central aspect of GAL regulation and a focal point for the numerous factors and processes that contribute to it.

Chromatin↗
PubMed1997

The characterization of novel Pax genes of the sea urchin and Drosophila reveal an ancient evolutionary origin of the Pax2/5/8 subfamily.

The developmental control genes of the Pax family can be grouped into different subclasses according to structure and sequence homology. Here we describe the isolation and characterization of three novel Pax genes of the sea urchin for which no homologues are yet known in other animal phyla. One of these genes, suPaxB, codes for the previously characterized transcription factor TSAP which is involved in the developmental regulation of two pairs of late histone genes. Furthermore, conserved members of the Pax2/5/8 subfamily, which have so far been described only in vertebrates, were isolated not only from the sea urchin, but also from Drosophila and C. elegans. Hence, the Pax2/5/8 transcription factors constitute an ancient subfamily of highly conserved Pax proteins. During Drosophila embryogenesis, the Pax258 gene is shown to be expressed in the precursor cells of the external sensory organs, thus suggesting a role for Pax258 in the early development of the peripheral nervous system of insects.

Amino Acid Sequence↗
PubMed1986

A chimeric mouse histone H4 gene containing either an intron or poly(A) addition signal behaves like a basal histone.

We have modified the basic structure of the mouse H4 histone gene by introducing, in one case, the IVS-II of the human beta globin gene in the middle of the H4 coding region and, in the second case, the poly(A) addition signal from either the chicken vimentin gene or the alpha globin gene, displacing the hairpin loop structure in the 3' direction. Constructs were placed into the vector, PSV2gpt, and stably transformed into L cells. Pools of 100-500 independent transformants were analyzed for H4 expression. Even though the intron is processed correctly, the growth regulated expression of the modified gene is lost and the gene is now expressed at a constant basal level. Furthermore, unprocessed transcripts accumulate in the nucleus of Go cells when compared to exponentially growing cultures. Polyadenylated H4 RNA is correctly processed but expressed at reduced levels (30 fold) in a constitutive manner, independent of the growth state of the cell. The altered expression of these chimeric H4 genes compared to the endogenous copy or the transfected wild type gene suggests a structural model to explain the cell cycle independent expression of the basal histones.

Animals↗
PubMed1997

Tandem arrangement of two genes encoding kinetoplast-associated H1 histone-like proteins.

Crithidia fasciculata proteins p18 and p17 are associated with kinetoplast DNA and are encoded by genes KAP2 and KAP3, respectively. Polymerase chain reaction (PCR) amplification using primers within the coding sequences of each gene revealed that the KAP2 and KAP3 genes are linked on the same chromosomal DNA and are separated by a 1.8 kb intergenic region containing several long homopolymer tracts. The KAP2 gene has a 3'UTR of more than 1.1 kb or almost three times as long as the KAP2 coding sequence. Several restriction enzyme polymorphisms in this region of the chromosome are the result of sequence differences between the two alleles of the KAP2 gene. The predicted amino-acid sequences of alleles KAP2-1 and KAP2-2 differ by three non-conservative amino acid substitutions in the highly basic carboxyl tail of the protein and suggest that the protein products could have different physical and biological properties. The KAP2 and KAP3 genes have different patterns of mRNA expression during the cell cycle with the KAP3 transcript varying periodically during the cell cycle in the same manner as transcripts of several kinetoplast and nuclear DNA replication genes.

Alleles↗
PubMed1985

Faithful cell-cycle regulation of a recombinant mouse histone H4 gene is controlled by sequences in the 3'-terminal part of the gene.

We have analyzed the expression of endogenous histone H4 genes and of a newly introduced H4 gene in 21-Tb cells, a mouse mastocytoma cell-cycle mutant. Endogenous H4 mRNAs were less abundant by a factor of 120-180 in G1-arrested than in exponentially multiplying cells. However, H4 transcription rates were only decreased by a factor of 3 under these conditions, as determined by in vitro elongation of nascent transcripts. This indicates that post-transcriptional control of histone mRNA levels is important, in accord with published data. We introduced a mouse H4 gene, modified by a 12-base-pair (bp) insertion in its coding sequence, into 21-Tb cells by DNA-mediated gene transfer. The levels of transcripts from this gene were regulated in parallel with those of the endogenous genes. Moreover, fusion of the simian virus 40 (SV40) early promoter to a 463-bp fragment containing the 3'-terminal half of the mouse H4 gene, including 230 bp of spacer sequences, led to the regulated expression of SV40/H4 fusion RNA. However, a small proportion of SV40-initiated transcripts were not processed to histone-specific 3' ends, but extended farther through the downstream Escherichia coli galactokinase gene to a SV40 polyadenylylation site. In contrast to the short SV40/H4 RNA, the levels of these longer transcripts were not reduced in G1-arrested cells. These results show that sequences in the 3'-terminal part of the H4 gene can regulate gene expression in the cell cycle, presumably at the post-transcriptional level, as long as they are not positioned much more distant from the terminus than normal.

Animals↗
PubMed1982

Generation of authentic 3' termini of an H2A mRNA in vivo is dependent on a short inverted DNA repeat and on spacer sequences.

We have determined what sequences are required to generate the authentic 3' termini of a sea urchin H2A histone mRNA. We have constructed a series of deletion and insertion mutants in the cloned histone repeat unit h22 of Psammechinus miliaris and have analyzed the transcripts of both wild-type and mutant DNAs produced in the frog oocyte. The protein-coding sequences of the H2A gene can be removed without any deleterious effects on transcription initiation or termination. A 12 bp deletion, which removes a highly conserved inverted DNA repeat immediately preceding the H2A mRNA 3' terminus, elicits read-through of the polymerase into the spacer DNA further downstream. However, the inverted repeat and the sequence coding for the 3' terminus of the mRNA are by themselves not sufficient to generate faithful 3' ends. Our data suggest that spacer sequences downstream of the 3' mRNA terminus are required as well.

Animals↗
PubMed2003

A short-range gradient of histone H3 acetylation and Tup1p redistribution at the promoter of the Saccharomyces cerevisiae SUC2 gene.

Chromatin immunoprecipitation assays are used to map H3 and H4 acetylation over the promoter nucleosomes and the coding region of the Saccharomyces cerevisiae SUC2 gene, under repressed and derepressed conditions, using wild type and mutant strains. In wild type cells, a high level of H3 acetylation at the distal end of the promoter drops sharply toward the proximal nucleosome that covers the TATA box, a gradient that become even steeper on derepression. In contrast, substantial H4 acetylation shows no such gradient and extends into the coding region. Overall levels of both H3 and H4 acetylation rise on derepression. Mutation of GCN5 or SNF2 lead to substantially reduced SUC2 expression; in gnc5 there is no reduction in basal H3 acetylation, but large reductions occur on derepression. SNF2 mutation has little effect on H3 acetylation, so SAGA and SWI/SNF recruitment seem to be independent events. H4 acetylation is little affected by either GCN5 or SNF2 mutation. In a double snf2/gcn5 mutant (very low SUC2 expression), H3 acetylation is at the minimal level, but H4 acetylation remains largely unaffected. Transcription is thus linked to H3 but not H4 acetylation. Chromatin immunoprecipitation assays show that Tup1p is evenly distributed over the four promoter nucleosomes in repressed wild type cells but redistributes upstream on derepression, a movement probably linked to its conversion from a repressor to an activator.

Adenosine Triphosphatases↗
PubMed1997

The gene for histone RNA hairpin binding protein is located on human chromosome 4 and encodes a novel type of RNA binding protein.

The hairpin structure at the 3' end of animal histone mRNAs controls histone RNA 3' processing, nucleocytoplasmic transport, translation and stability of histone mRNA. Functionally overlapping, if not identical, proteins binding to the histone RNA hairpin have been identified in nuclear and polysomal extracts. Our own results indicated that these hairpin binding proteins (HBPs) bind their target RNA as monomers and that the resulting ribonucleoprotein complexes are extremely stable. These features prompted us to select for HBP-encoding human cDNAs by RNA-mediated three-hybrid selection in Saccharomyces cerevesiae. Whole cell extract from one selected clone contained a Gal4 fusion protein that interacted with histone hairpin RNA in a sequence- and structure-specific manner similar to a fraction enriched for bovine HBP, indicating that the cDNA encoded HBP. DNA sequence analysis revealed that the coding sequence did not contain any known RNA binding motifs. The HBP gene is composed of eight exons covering 19.5 kb on the short arm of chromosome 4. Translation of the HBP open reading frame in vitro produced a 43 kDa protein with RNA binding specificity identical to murine or bovine HBP. In addition, recombinant HBP expressed in S. cerevisiae was functional in histone pre-mRNA processing, confirming that we have indeed identified the human HBP gene.

Amino Acid Sequence↗
PubMed1985

Organization, primary structure, and evolution of histone H2A and H2B genes of the fission yeast Schizosaccharomyces pombe.

The histone H2A and H2B genes of the fission yeast Schizosaccharomyces pombe were cloned and sequenced. Southern blot and sequence analyses showed that, unlike other eucaryotes, Saccharomyces cerevisiae included, S. pombe has unequal numbers of these genes, containing two histone H2A genes (H2A-alpha and -beta) and only one H2B gene (H2B-alpha) per haploid genome. H2A- and H2B-alpha are adjacent to each other and are divergently transcribed. H2A-beta has no other histone gene in close proximity. Preceding both H2A-alpha and -beta is a highly conserved 19-base-pair sequence (5'-CATCAC/AAACCCTAACCCTG-3'). The H2A DNA sequences encode two histone H2A subtypes differing in amino acid sequence (three residues) and size (H2A-alpha, 131 residues; H2A-beta, 130 residues). H2B-alpha codes for a 125-amino-acid protein. Sequence evolution is extensive between S. pombe and S. cerevisiae and displays unique patterns of divergence. Certain N-terminal sequences normally divergent between eucaryotes are conserved between the two yeasts. In contrast, the normally conserved hydrophobic core of H2A is as divergent between the yeasts as between S. pombe and calf.

Amino Acid Sequence↗
PubMed1989

Expression of a mouse replacement histone H3.3 gene with a highly conserved 3' noncoding region during SV40- and polyoma-induced Go to S-phase transition.

We have isolated and sequenced a mouse replacement variant histone H3.3 cDNA. It corresponds to the most abundant mRNA expressed from a unique gene by the use of one out of three polyadenylation sites. The 3' non coding region of H3.3 is very long (approximately 1100 nt) and highly conserved throughout evolution since it is about 95% homologous to the 3' non coding region of the chicken H3.3B gene. We studied the expression of the H3.3 gene during SV40- and polyoma-induced mitotic host reaction in confluent, Go-arrested primary mouse kidney cell cultures. H3.3 replacement variant mRNA steady state levels increased during the Go to S-phase transition, apparently as the result of two mechanisms: one related to cell growth, whereas the other was linked to cellular DNA synthesis. The latter mechanism was however far less pronounced than with replication histone variant mRNAs. The biological implications of these results are discussed.

Amino Acid Sequence↗
PubMed2003

Scaffold attachment factor A (SAF-A) is concentrated in inactive X chromosome territories through its RGG domain.

Female mammalian cells inactivate transcription from one of their X chromosomes to equalize gene expression of X-linked genes between males and females. Inactivation is a multistep process that involves a large non-coding RNA termed XIST, a variety of epigenetic modifications of chromatin, and alterations in protein composition such as enrichment of the histone variant macroH2A. We show here that inactive X chromosomes are also enriched in a well-characterized protein component of the nuclear scaffold, SAF-A. This protein has been implicated in chromatin organization, owing to its high specificity for scaffold-associated region (SAR)-DNA, in transcriptional regulation, e.g. of hormone-regulated genes, owing to its functional interaction with steroid receptors, and in RNA processing, owing to its interaction with RNA and heterogeneous nuclear ribonucleoprotein (hnRNP) particles. After near complete removal of DNA and associated chromatin proteins such as macroH2A, SAF-A remains with the "nuclear matrix", still highlighting the former position of inactive X chromosomes. Interestingly, the enrichment of SAF-A in the inactive X chromosome depends on the RNA binding domain of the protein, the RGG box, raising the possibility that interaction of SAF-A with XIST RNA may contribute to the silencing of X-linked genes by local changes in nuclear architecture.

Cells, Cultured↗
PubMed1993

Construction of nucleosome cores from defined sequence DNA of viral origin.

The de novo construction of defined nucleosomes from two DNA fragments of simian virus SV40 is described. One fragment spans the region containing the origin of replication of the virus from base -16 to base 161, a region which is nucleosome-free during virus replication. The other fragment, of 142 bp (1352 to 1493), is within the region coding for viral proteins VP2 and VP3, and serves for comparison. Both fragments form nucleosomes with similar efficiency when combined with histone cores as well as when exchanged with existing core particles. The DNase I digestion pattern and exonuclease III analysis both indicate that true nucleosome cores are formed, and that a prolonged tail is not protruding from the constructs. The efficient formation of a nucleosome core particle from the origin region of DNA implies that the absence of nucleosomes from this region during viral infection is not prescribed by the specific base sequence of origin DNA, and is therefore likely to be determined by non-histone nuclear factors associated with the SV40 replication process.

Base Sequence↗
PubMed1991

Nucleotide sequences of two members of the chicken H4 histone-encoding gene family.

The nucleotide sequences of two genes (H4-III and H4-IV) from the chicken H4 histone-encoding gene family have been determined. The four H4 genes, including the previously sequenced H4-I and H4-II genes, encode the same amino acid sequence and possess several copies of the possible Sp1-binding sequences on the coding and noncoding strands within the 5'-flanking regions.

Amino Acid Sequence↗
PubMed1989

Characterization of poly(ADP-ribosyl)ated domains of rat pachytene chromatin.

Poly(ADP-ribosyl)ation of nuclear proteins was several-fold higher in the pachytene spermatocytes than in the premeiotic germ cells of the rat. Among the histones of the pachytene nucleus, histone subtypes H2A, H1 and H3 were poly(ADP-ribosyl)ated. Based on the immunoaffinity fractionation procedure of Malik, Miwa, Sugimara & Smulson [(1983) Proc. Natl. Acad. Sci. U.S.A. 80, 2554-2558] we have fractionated DNAase-II-solubilized chromatin into poly(ADP-ribosyl)ated chromatin (PAC) and non-poly(ADP-ribosyl)ated chromatin (non-PAC) domains on an anti-[poly(ADP-ribose)] IgG affinity matrix. Approx. 2.5% of the pachytene chromatin represented the PAC domains. A significant amount of [alpha-32P]dATP-labelled pachytene chromatin (labelled in vitro) was bound to the affinity matrix. The DNA of pachytene PAC domains had internal strand breaks, significant length of gaps and ligatable ends, namely 5'-phosphoryl and 3'-hydroxyl termini. On the other hand, the PAC domains from 18 h regenerating liver had very few gaps, if any. The presence of gaps in the pachytene PAC DNA was also evident from thermal denaturation studies. Although many of the polypeptides were common to the PAC domains of both pachytene and regenerating liver, the DNA sequences associated with these domains were quite different. A 20 kDa protein and the testis-specific histone H1t were selectively enriched in the pachytene PAC domains. The pachytene PAC domains also contained approx. 10% of the messenger coding sequences present in the DNAase-II-solubilized chromatin. The pachytene PAC domains, therefore, may represent highly enriched DNA-repair domains of the pachytene nucleus.

Animals↗