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M Bustin

Publications and source records attributed to M Bustin.

At least 127 records · Page 7Linked to original sources

Inhibition of transcription in somatic cells by microinjection of antibodies to chromosomal proteins.

The in vivo function of defined chromosomal proteins was examined by microinjecting purified antibody and antibody fragments into living fibroblasts. The involvement of histones and chromosomal high mobility group proteins HMG-1, 2, and 17 in transcription was visualized by studying the [3H]uridine incorporation in KD human fibroblasts after microinjection of fluoresceinated antibodies to these proteins. Nuclear uridine incorporation was not affected by microinjection of control antibodies or by the presence of immune complexes formed after microinjection of antibodies to chromosomal proteins that are not involved in transcription. In contrast, injection of anti-histone IgG, F(ab')2, or Fab and anti-HMG-17 IgG causes a significant reduction in transcription. The reduction is proportional to the amount of antibody introduced into the cell. We conclude that histones and protein HMG-17 are present on transcribed regions of the genome and that passage of RNA polymerase along the chromatin fiber is prevented by antibody binding to these proteins.

Antibodies↗

High mobility group proteins of amphibian oocytes: a large storage pool of a soluble high mobility group-1-like protein and involvement in transcriptional events.

Oocytes of several amphibian species (Xenopus laevis, Rana temporaria, and Pleurodeles waltlii) contained a relatively large pool of nonchromatin-bound, soluble high mobility group (HMG) protein with properties similar to those of calf thymus proteins HMG-1 and HMG-2 (protein HMG-A; A, amphibian). About half of this soluble HMG-A was located in the nuclear sap, the other half was recovered in enucleated ooplasms. This protein was identified by its mobility on one- and two-dimensional gel electrophoresis, by binding of antibodies to calf thymus HMG-1 to polypeptides electrophoretically separated and blotted on nitrocellulose paper, and by tryptic peptide mapping of radioiodinated polypeptides. Most, if not all, of the HMG-A in the soluble nuclear protein fraction, preparatively defined as supernatant obtained after centrifugation at 100,000 g for 1 h, was in free monomeric form, apparently not bound to other proteins. On gel filtration it eluted with a mean peak corresponding to an apparent molecular weight of approximately 25,000; on sucrose gradient centrifugation it appeared with a very low S value (2-3 S), and on isoelectric focusing it appeared in fractions ranging from pH approximately 7 to 9. This soluble HMG-A was retained on DEAE-Sephacel but could be eluted already at moderate salt concentrations (0.2 M KCl). In oocytes of various stages of oogenesis HMG-A was accumulated in the nucleus up to concentrations of approximately 14 ng per nucleus (in Xenopus), corresponding to approximately 0.2 mg/ml, similar to those of the nucleosomal core histones. This nuclear concentration is also demonstrated using immunofluorescence microscopy. When antibodies to bovine HMG-1 were microinjected into nuclei of living oocytes of Pleurodeles the lateral loops of the lampbrush chromosomes gradually retracted and the whole chromosomes condensed. As shown using electron microscopy of spread chromatin from such injected oocyte nuclei, this process of loop retraction was accompanied by the appearance of variously-sized and irregularly-spaced gaps within transcriptional units of chromosomal loops but not of nucleoli, indicating that the transcription of non-nucleolar genes was specifically inhibited by this treatment and hence involved an HMG-1-like protein. These data show that proteins of the HMG-1 and -2 category, which are usually chromatin-bound components, can exist, at least in amphibian oocytes, in a free soluble monomeric form, apparently not bound to other molecules. The possible role of this large oocyte pool of soluble HMG-A in early embryogenesis is discussed as well as the possible existence of soluble HMG proteins in other cells.

Amphibians↗

Immunological detection of carcinogen-modified DNA fragments after in vivo modification of cellular and viral chromatin.

Antibodies specific for DNA modified by (+/-)-trans-7, 8-dihydrobenzo(a)pyrene-7,8-diol-9, 10-epoxide have been used to quantitate the relative modification level in fragments derived from pBR322 DNA from cellular DNA and in the coding and noncoding strands of simian virus 40 DNA. DNA fragments with a covalent molar modification level ranging from less than 1 to over 200 are resolved by agarose gel electrophoresis and transferred to diazobenzyloxymethyl cellulose paper. The paper is incubated with antibodies specific to carcinogen-modified DNA, and the location of the antibody is visualized by autoradiography after incubation with 125I-protein A. The binding of antibodies is directly proportional to the level of DNA modification. Using this technique, we find that linker DNA is about 2.5- to 3-fold more accessible to (+/-)-trans-7,8-dehydrobenzo(a)pyrene-7, 8-diol-9, 10-epoxide than nucleosomal core DNA and that under in vivo conditions the coding and noncoding strands of the simian virus 40 chromosome are equally accessible to trans-7,8-dihydrobenzo[a]pyrene-7,8-diol-9, 10-epoxide. The approach described allows assessment of the relative level of modification in any DNA sequence which can be subjected to gel electrophoresis.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

Antigenic determinants of high mobility group chromosomal proteins 1 and 2.

The antigenic determinants of nonhistone high mobility group chromosomal proteins 1 (HMG-1) and 2 (HMG-2) were studied with rabbit antisera elicited against HMG-1 and against HMG-2 and monoclonal antibodies elicited by HMG-1. The monoclonal antibodies did not distinguish between the two proteins, suggesting that they have specificity toward a shared determinant. Whereas anti-HMG-1 did not, anti-HMG-2 did distinguish between the proteins, suggesting that the anti-HMG-2 serum contains antibodies against peptides which differ between the proteins. Peptides were generated from HMG-1 and HMG-2 by controlled digestion with trypsin and pepsin. Analysis of the digests by ELISA and by sodium dodecyl sulfate electrophoresis followed by diazobenzyloxymethyl transfer, antibody binding and autoradiography revealed that most of the antibodies are against sequential determinants some of which are smaller than 3000 in molecular weight.

Animals↗

Antibodies against the folding domain of histone H5 cross-react with H1(0) but not with H1.

Antibodies to the folding domain (residues 22-100) of histone H5 were elicited in rabbits. Analysis of the specificity of these antibodies by enzyme-linked immunoassay and by diazobenzyloxymethyl cellulose transfer techniques revealed that the antibody cross-reacts strongly with intact H5 and histones H1(0)a and H1(0)b purified from ox liver but not with the four core calf thymus, or with high mobility group proteins. We conclude that the globular region of H5 is serologically homologous to that of H1 degrees and suggest that possible functional similarities between the two proteins reside in this region.

Animals↗

Antibody to poly(adenosine diphosphate-ribose) polymerase and its use in chromatin analysis.

To facilitate investigations on the organization of poly (ADP-Rib) polymerase in chromatin, and to elucidate its biological function, polymerase purified from HeLa nuclei was used to elicit antibodies in mice. The anti-polymerase sera was found to be specific by multiple criteria. The association of polymerase with oligonucleosomes of differing chain size was determined by the specific binding of polymerase antibody (and as control, anti-histone H3) to nitrocellulose transfers of native electrophoretic gels of these particles. By this technique, polymerase appears to be associated with a select subclass of nucleosomes. Further resolution of the polymerase binding sites within nucleosome classes was achieved with the antibody by two-dimensional native polyacrylamide gel electrophoresis and nitrocellulose transfer.

Antibodies↗

Autoantibodies to nucleosomal proteins: antibodies to HMG-17 in autoimmune diseases.

The relative amounts of autoantibodies against defined nucleosomal proteins present in serums from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and mixed connective tissue disease (MCTD) have been examined by an enzyme-linked immunoassay. Autoantibodies to nucleosomal proteins were detected in 45 percent of the patients with SLE, 18 percent of the MCTD patients, and none of the RA patients. The results suggest that, in SLE, antibodies are formed against a subset of nucleosomes which contain protein HMG-17.

Arthritis, Rheumatoid↗

Immunochemical detection of chromosomal protein HMG-17 in chromatin subunits.

Chromosomal protein HMG-17, purified from calf thymus, has been used to elicit specific antibodies in rabbits. Specific serological reaction between the antigen and the antisera is demonstrated by solid-phase radioimmunoassay and by competitive inhibition assays. The antisera did not cross-react with histones or other chromosomal HMG proteins. The antisera bound specifically to chromatin subunits isolated from HeLa cells, demonstrating that it may be used to study the in situ organization of this chromosomal protein. Chromatin purified from HeLa nuclei was digested with micrococcal nuclease, and the resulting mono- and oligonucleosomes were fractionated on a sucrose gradient. Analyses of the content of chromosomal proteins HMG-1, HMG-17, and H4 in different size nucleosomal particles, by the solid-phase radioimmunoassay, reveal that the distribution of HMG-17 was the same as that of H4, but different from that of HMG-1.

Animals↗

Localization of chromosomal protein HMG-1 in polytene chromosomes of Chironomus thummi.

The distribution of accessible antigenic sites in the chromosomal protein high mobility group one (HMG-1) in Chironomus thummi polytene chromosomes is visualized by immunofluorescence. The results indicate that (a) HMG-1 is distributed in a distinct banding pattern along the entire length of the chromosomes; (b) the banding pattern obtained with fluorescent antibody does not strictly correspond to that observed by phase-contrast microscopy; and (c) the amount of HMG-1 increases, and the fluorescent banding pattern changes, during the development of the organism. Our findings suggest that the protein may be involved in the modulation of the structure of selected loci in the chromosome.

Animals↗

Immunochemical visualization of binding of the chemical carcinogen benzo(a)pyrene diol-epoxide 1 to the genome.

antisera against DNA modified with r-7,t-8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE-1) was elicited in rabbits. Such sera reached with either single- or double-stranded modified DNA but not with unmodified DNA, free benzo(a)pyrene, or proteins modified by BPDE-1. Indirect immunofluorescence studies indicated that the immunoglobulin G in the sera bound specifically to the nuclei of KD cells which were treated with BPDE-1. The intensity of fluorescence was proportional to the dose of BPDE-1 used to treat the cells. About 50% of the BPDE-1-DNA adducts remained bound to DNA 24 hr after the removal of the carcinogen. The location of BPDE-1-modified bases in Col E1 DNA was visualized by immunoelectron microscopy.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

Chromatin subunits elicit species-specific antibodies against nucleoprotein antigenic determinants.

Nucleosomes composed of 195 base pairs of DNA associated with histones H2A, H2B, H3, and H4 purified from chicken erythrocyte nuclei were used to elicit antibodies in rabbits. Specific serological reaction between the antisera and the nucleosomes is demonstrated by immunodiffusion, immunofluorescence, microcomplement fixation, solid-phase radioimmunoassay, immunosedimentation, and polyacrylamide gel electrophoresis of 5'-32P end-labeled nucleosomes. The antisera did not react with DNA extracted from these nucleosomes, core histones, or the cross-linked histone octamer from chicken erythocytes, calf thymus total histones, or chromosomal proteins HMG-1 or HMG-17. Nucleosome antigenicity was not affected by redigestion with micrococcal nuclease. Digestion with DNase I brought about 50% loss of reactivity while digestion with trypsin or proteinase K resulted in total loss of activity. The antisera reacted strongly with trimer, dimer, and monomer nucleosomes as well as with the core particle (145 base pairs of DNA) and subnucleosome (greater than 145 base pairs) obtained from chicken. It reacted less well with nucleosomes obtained from HeLa cells and was almost totally devoid of activity against chromatin particles obtained from rat liver or wheat germ. Experiments employing the technique of transferring proteins from a polyacrylamide gel to diazobenzyloxymethyl paper and visualization of antigens by autoradiography excluded the possibility that the serum contains antibodies against tissue-specific antigens which are found in small amounts but are very immunogenic. It is concluded that most of the anitbodies in the sera are directed against nucleoprotein antigenic determinants composed of the N-terminal portion of the histones and segments of DNA. Antibody binding is dependent on contact between the histone and DNA segments and is independent of the integrity of the entire nucleosome. Thus, certain histone DNA contacts remain intact even though the structure of the nucleosome has been disrupted.

Animals↗

High mobility group chromosomal proteins isolated from muclei and cytosol of cultured hepatoma cells are similar.

Using sequential chromatography on columns containing immobilized double-stranded DNA and single-stranded DNA, we have purified a protein from the cytosol of an established line of cultured rat hepatoma cells that, by several criteria, is a high mobility group (HMG) protein. Analyses of DNA binding properties, electrophoretic mobilities, amino acid compositions, and immunochemical reactivities reveal that the cytosolic protein is the same protein as HMG-1 isolated from the purified chromatin of the same cell line. Thus, authentic HMG-1 appears to be at least partially responsible for the cytoplasmic fluorescence observed when mammalian cells are stained with fluorescece observed when mammalian cells are stained with fluorescent-labeled, affinity-purified antibodies against HMG-1 [Bustin, M., & Neihart, N.K. (1979) Cell 16, 181-189]. We suggest that HMG-1 cn shuttle between nucleus and cytoplasm, perhaps in response to the nucleus' need for helix destabilizing proteins.

Amino Acids↗

Antigenicity of histones in various chromatins.

Antisera specific to purified histone fractions are used to assess the antigenicity of the histones present in chromatin derived from various sources. The results indicate that the antigenicity of the histones present in chromatin is markedly diminished as compared to the antigenicity of the histones free in solution. The antigenicity of histones in chromatins derived from three different tissues of the rat is very similar. The antigenicity of the histones present in chromatin derived from calf thymus is higher than that of the histones present in rat thymus. It is concluded that the major reason for diminished antigenicity of histones in chromatin is that the histones are complexed in the nucleosome conformation and that the antigenic determinants residing in histones in various chromatins are exposed to similar degrees.

Animals↗

Solid phase radioimmunoassay for chromosomal components.

This manuscript describes the use of a solid phase radioimmunoassay for serological analysis of chromosomal components. The applicability of this assay for various studies on nonhistone chromosomal proteins, histones, and chromatin subunits is illustrated. By this technique it is possible to detect and quantify nuclear antigens in the nanogram range. The assay has all the inherent sensitivity and precision of radioimmunoassays and, as such, introduces a new, convenient method for serological analyses of chromosomal components. The results presented reconfirm the serological similarity among the HMG (high mobility group) proteins derived from various sources. The amount of HMG proteins present in mononucleosomes purified from calf thymus is similar to that present in mononucleosomes purified from HeLa cells, suggesting that various tissues contain similar amounts of these proteins. Per nucleosome, dinucleosomes and trinucleosomes contain as much HMG-1 protein as mononucleosomes, suggesting that the protein is not exclusively associated with those regions of DNA which have been solubilized by micrococcal nuclease. Part of the antigenic determinants present in HMG-1 forming a complex in the nucleosomal conformation do not interact with antibodies.

Animals↗

Concanavalin A binds to puffs in polytene chromosomes.

CHANGES in transcriptional activity at defined loci are often correlated with significant local structural changes in the genome(1), and in polytene chromosomes, such changes are thought to be associated with compositional or conformational changes in the protein complement at these particular bands(2,3). Thus, various studies on Balfoiani rings and specific 'puffs' in such chromosomes are useful for elucidating the role of defined chromosomal components in both chromosome structure and gene activity. Such studies require specific probes which will allow in situ localisation of a chromosomal component during the various stages of puffing. Antibodies specific to purified histone fractions(4-7), HMG proteins(8), RNA polymerase(9) and non-histone protein subfractions(10) have been used in studies on chromatin and chromosome structure. We reported previously that concanavalin A (Con A) specifically binds to three types of non-histone proteins present in chromatin purified from rat liver nuclei and suggested that derivatives of Con A might serve as specific probes to study the in situ organisation of these non-histone proteins(11). We have now reacted fluorescein-labelled Con A with polytene chromosomes isolated from different developmental stages of Chironomus thummi and visualised the location of the bound Con A by fluorescence microscopy. We observed that the fluorescent lectin, which has an affinity for glucose- and mannose-containing molecules, specifically bound to the transcriptionally active regions of chromosome IV. The extent of binding of Con A to the Balbiani rings present in regions b and c of chromosome IV is proportional to the size of the respective ring. Our results indicate that glucose- or mannose-containing molecules are present in these Balbiani rings and that the availability of these sugars to interact with Con A can be correlated with the developmental stage of a puff. We suggest that lectins can be useful cytological tools with which to study the in situ organisation of defined chromosomal components during various functional states of the genome.

Journal Article↗

Serological analysis of species specificity in the high mobility group chromosomal proteins.

The non-histone chromosomal protein of the high mobility group (HMG-1) present in mouse liver was purified to homogeneity. Antibodies against this protein as well as pure HMG-1 derived from calf thymus and HMG-E purified from duck erythrocytes were elicited in rabbits. The interaction between the antibodies and the immunogens was measured by passive hemoagglutination and by quantitative microcomplement fixation. Quantitative microcomplement fixation assays revealed that the immunological distance between HMG-1 from calf thymus and HMG-1 from mouse liver and duck erythrocytes was 15. This corresponds to 3% sequence differences. It was estimated that amino acid substitution occurred at about seven positions in the polypeptide chain. Thus, HMG-1 proteins display remarkable evolutionary conservation in their primary sequence, similar to that displayed by histones H4 and H3, suggesting that their biological function is dependent on stringent structural requirements. HMG-E protein is significantly different from both HMG-1 and HMG-2 derived from calf thymus. As such, it is a protein unique to avian erythrocytes.

Amino Acid Sequence↗