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PubMed2005

Dynamics of DNA repair suggested by the subcellular localization of Brca1 and Brca2 proteins.

The localization of proteins to specific subcellular compartments often reveals clues regarding their biological functions. Although significant progress has been made towards understanding how damaged DNA is repaired, experiments to date have primarily focused on signal transduction pathways that activate DNA repair protein complexes and on how these complexes are assembled. Current evidence suggests that certain DNA repair processes are spatially organized such that aberrant DNA structures can be brought into proximity with DNA repair proteins at fixed sites. Since biochemical evidence suggests that the tumor suppressor proteins, Brca1 and Brca2, may mediate the assembly of protein complexes involved in the repair of damaged DNA, we have performed subcellular fractionation experiments to determine the subnuclear localization of these proteins. The majority of Brca1 and Brca2 proteins were found to interact tightly with the nuclear matrix. Furthermore, within the limits of detection, localization of Brca1 and Brca2 to the nuclear matrix was not altered following treatment of cells with DNA damaging agents that activate homology-mediated double-stranded DNA break and transcription-coupled repair pathways. Our findings suggest that Brca1 and Brca2 may perform their DNA repair-related functions from positions that are anchored to the nuclear matrix. These data are consistent with proposed models that suggest that components of specific repair complexes residing on the nuclear matrix function to recruit damaged DNA.

Animals↗
PubMed1994

Transcription factor binding sites in the matrix attachment region (MAR) of the chicken alpha-globin gene.

Nuclear matrix is a nuclear protein-DNA superstructure believed to be the exclusive site of DNA replication, transcription, repair, and recombination. The attachment regions of chromatin loops to the nuclear matrix, called MARs, nest origins of replication, have transcriptional enhancer activity, and via their interaction with protein transcription factors may govern gene switch during development and tissue-specific gene expression. In this study the 967 bp MAR of the chicken alpha-globin gene is analyzed for the presence of hexanucleotides from a number (83 in total) of vertebrate protein transcription factors and core origins of replication. A total number of 760 hexanucleotides from factor sites or origins of replication were used for this search. We found that: (1) The occurrence of protein transcription factor binding sites overall on the MAR fragment as well as on the enhancer and promoter regions of other genes is only about 1.2-1.5 times higher than in random DNA, something consistent for all MAR and enhancer sequences examined. However, a high concentration (up to 2.7 times over random sequences) of hexanucleotide factor sites is observed on small stretches of the alpha-globin gene MAR. (2) Some regulatory protein binding sites are underrepresented whereas others are overrepresented, giving to an MAR a particular transcription factor flavor. (3) The DNA curvature map of the MAR sequence and the potential sites of positioned nucleosomes suggest the sites where a competition between core histone octamers and protein transcription factors for DNA might be found. This approach might provide a novel technique to diagnose for the regulatory or nonregulatory function of a stretch of DNA. Furthermore, MARs are proposed to constitute important regulatory elements of genes in addition to enhancers, promoters, silencers, locus control regions, and origins of replication. Additional parameters such as interaction of a transcription factor with other transcription factors fixed at vicinal sites, DNA methylation, intrinsic DNA curvature torsional strain, and nucleosome positioning might also determine the high-affinity binding of a transcription factor to its functional sites and its exclusion from or low affinity binding to other nonregulatory regions.

Animals↗
PubMed1994

Novel action of retinoic acid. Stabilization of newly synthesized alkaline phosphatase transcripts.

Several observations led us to investigate the possibility that retinoic acid achieved its marked induction of alkaline phosphatase gene expression through a post-transcriptional effect in the nuclei of clonal rat pre-osteoblastic UMR 201 cells. The steady-state level of alkaline phosphatase mRNA was significantly stimulated by retinoic acid. Although nuclear run-on analysis showed that 10(-6) M retinoic acid caused an increase in alkaline phosphatase gene transcription, this was transient compared with the rise in alkaline phosphatase mRNA which continued to accumulate for many hours after retinoic acid stimulation of gene transcription had ceased. Moreover, the modest increase in transcriptional rate (approximately 2-fold) was not sufficient to account for the magnitude of the rise in mRNA level. In order, therefore, to examine the influence of retinoic acid on nuclear processing events, a cellular subfractionation method was applied. By nuclease protection analysis, and also by using reverse transcription-polymerase chain reaction, sequences corresponding to intron 2 and intron 4, respectively, were demonstrated specifically in the nuclear matrix fraction of both control and retinoic acid-treated cells. Mature (spliced) alkaline phosphatase mRNA accumulated in the non-matrix (DNase I/salt eluate, nuclear membrane) and cytoplasmic fractions of retinoic acid-treated cells at more than 100-fold greater levels than in control cells. This implies that nuclear processing of the primary RNA transcript occurred only in cells treated with retinoic acid. The post-transcriptional action of retinoic acid was inhibited by cotreatment with 10 micrograms/ml cycloheximide. Transforming growth factor beta (TGF beta) (1 ng/ml) did not influence whole cell alkaline phosphatase levels in UMR 201 cells. Nevertheless, TGF beta increased the transcriptional rate of the alkaline phosphatase gene. Although precursor mRNA was detected in the nuclear matrix fraction of TGF beta-treated cells, there was no evidence of further mRNA nuclear processing. The data are consistent with stabilization of nascent alkaline phosphatase mRNA chains by retinoic acid treatment and suggests that regulation of mRNA processing can be independent of gene transcription. This study demonstrates a novel post-transcriptional action of retinoic acid which plays an important, if not a dominant role, in determining the steady-state level of alkaline phosphatase mRNA.

Alkaline Phosphatase↗
PubMed1989

Chromatin architecture and nuclear RNA.

The maintenance of normal chromatin morphology requires ongoing RNA synthesis. We have examined the role of RNA in chromatin organization, using selective detergent extraction of cells, RNA synthesis inhibitors, and enzymatic digestion of nuclear RNA. Comparison of extracted and unextracted cells showed that the important features of chromatin architecture were largely unchanged by the extraction procedure. Normally, chromatin was distributed in small heterochromatic regions and dispersed euchromatic strands. Ribonucleoprotein granules were dispersed throughout the euchromatic regions. Exposure to actinomycin led to the redistribution of chromatin into large clumps, leaving large empty spaces and a dense clustering of the remaining ribonucleoprotein granules. When the nuclei of extracted cells were digested with RNase A, there was a rearrangement of chromatin similar to but more pronounced than that seen in cells exposed to actinomycin. The inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidizole also inhibits RNA synthesis but by a different mechanism that leaves no nascent RNA chains. The drug had little effect on chromatin after brief exposure but resembled actinomycin in its effect at longer times. We also examined the structure of the nuclear matrix to which most heteronuclear RNA remains associated. Pretreatment of cells with actinomycin or digestion of the nuclear matrix with RNase A caused the matrix fibers to collapse and aggregate. The experiments show a parallel decay of chromatin and of nuclear matrix organization with the depletion of nuclear RNA and suggest that RNA is a structural component of the nuclear matrix, which in turn may organize the higher order structure of chromatin.

Cell Nucleus↗
PubMed2005

Differential intranuclear organization of transcription factors Sp1 and Sp3.

Sp1 and Sp3 are ubiquitously expressed mammalian transcription factors that activate or repress the expression of a variety of genes and are thought to compete for the same DNA binding site. We used indirect immunofluorescence microscopy and image deconvolution to show that Sp1 and Sp3 are organized into distinct nonoverlapping domains in human breast and ovarian cells. Domains of Sp1 and Sp3 infrequently associate with sites of transcription. Sp3 partitions with the tightly bound nuclear protein fraction of hormone responsive MCF-7 breast cancer cells, whereas only a subpopulation of Sp1 is found in that fraction. Both Sp1 and Sp3 are bound to the nuclear matrix, and the nuclear matrix-associated sites of Sp1 and Sp3 are different. Indirect immunofluorescence studies demonstrate that Sp1 and Sp3 associate with histone deacetylases 1 and 2 and with the estrogen receptor alpha, albeit at low frequencies in MCF-7 cells. Chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that although both Sp1 and Sp3 bind to the estrogen-responsive trefoil factor 1 promoter in MCF-7 cells, they do not occupy the same promoter. Our results demonstrate the different features of Sp1 and Sp3, providing further evidence that Sp3 is not a functional equivalent of Sp1.

Cell Line, Tumor↗
PubMed1984

Tumor promoters induce a specific morphological signature in the nuclear matrix-intermediate filament scaffold of Madin-Darby canine kidney (MDCK) cell colonies.

Tumor promoters such as phorbol 12-tetradecanoate 13-acetate (TPA), mezerein, teleocidin, aplysiatoxin, and benzoyl peroxide, although structurally unrelated, induce similar, profound changes in morphology in differentiated epithelial Madin-Darby canine kidney (MDCK) cell colonies. The alteration is evident in the organization of intermediate filaments in intact cells and in whole mounts of the nuclear matrix-intermediate filament (NM-IF) scaffold of the epithelial sheet. This substructure, obtained by salt extraction of the cytoskeletal framework, represents only 5% of the total cell protein but contains all of the intermediate filaments, nuclear matrix, and desmosomal core proteins arranged essentially as in the intact cell. The NM-IF is profoundly reorganized after exposure to TPA and retains the morphological changes observed in intact cells. These include bundling of the intermediate filaments, disruption of cell-cell borders, and marked deformation of the polygonal geometry of epithelia. Thus, TPA and all other complete or second-stage tumor promoters examined have a characteristic morphological signature that is not induced by mitogens, metabolic inhibitors, or agents known to disrupt microtubules or microfilaments. This signature, characteristic of tumor promoters, occurs in the absence of both protein and RNA synthesis. These results suggest that this response is prior to and independent of other biochemical markers for tumor promoters. Of the major filament systems, the cytokeratin network is implicated as an early or possibly primary site of tumor-promoter action because characteristics of the promoted cytoskeletal signature are observed in epithelial colonies after prior exposure to colchicine or cytochalasin D. Despite the massive reorganization of cytoskeletal morphology induced by TPA, the distribution of prelabeled proteins into structural fractions (i.e., cytoskeletal, chromatin, and the NM-IF) remains essentially unchanged. The sensitivity and specificity of the epithelial cell response suggest its possible use as a screen for promoting compounds.

Alkaloids↗
PubMed2000

On the relationship of matrix association and DNA replication.

The nuclear matrix is believed to contain sites of assembly of protein complexes that catalyze the initiation of DNA replication as well as DNA elongation. To explore this relationship, DNA replicated by human fibroblasts at the beginning of the S phase was purified and used to construct a cosmid library. Hybridization studies with a subgroup of clones (about one-sixth of the total clones in this library) showed that many of them were highlighted by probes prepared from early replicating DNA, as well as from nuclear matrix-associated DNA. Statistical analysis showed a positive correlation between these hybridization results. We seek to identify origins of replication that are activated early in the S phase of the cell cycle in human cells. Therefore, clones isolated from this library are being analyzed for the presence of structural motifs that have been found in other origins of replication and for potential sites of attachment to the nuclear matrix. This method of analysis is illustrated here using the published sequences for the origins of replication reported for the human lamin B2 and HPRT genes.

DNA Replication↗
PubMed1998

Fine structural analysis of DNA repair in mammalian cells.

Nucleotide excision repair (NER) of ultraviolet (UV) light induced photo lesions is heterogeneous in the genomic DNA. We have investigated the mechanistic basis for this repair heterogeneity by analyzing NER activity in higher order chromatin of repair proficient hamster cells. Immunological labeling of repair and transcription sites indicates that NER initiates at the nuclear matrix in close association with transcription. The repair gradually extends into the loop DNA regions in a time dependent fashion. Repair analysis indicates that the DNA damaged by UV irradiation is recruited to the nuclear matrix soon after UV exposure. Consistent with this finding, immunofluorescence and western blotting analyses indicate the enrichment of many NER proteins (XPA, RPA, PCNA, the P62 and p89 sub-units of the basal transcription factor, TFIIH) in the nuclear matrix of UV treated cells. These results strengthen the notion that the nuclear matrix is an important site for the assembly of an efficient repair complex.

Animals↗
PubMed1990

Drug and metabolite-induced perturbations in nuclear structure and function: a review.

Clarification of large-scale organization in cell nuclei is central to a full understanding of the mechanisms which underlie replication, transcription, and interaction with the cytoplasmic compartment. Many drugs and natural biological agents affect such processes directly, through inhibitory or stimulatory action, and often reveal structural and functional aspects in nuclei not otherwise apparent. There is increasing evidence that the pore complex - lamina of the nuclear matrix is a primary structural element during interphase, which is pivotal to most nuclear processes. This communication reviews evidence based on studies with drugs, inhibitors, and natural biological processes, that the nuclear matrix concept is indeed valid. It is further shown that despite diversity in mode of action and affected target cells, many compounds induce related or complementary changes in nuclei and that such uniformity in pattern is attributable to the nuclear matrix. A general model of the functional organization of the nucleus is presented, to account for the perturbations observed after mass interference with either transcription, replication, or protein synthesis.

Animals↗
PubMed1994

Multiple functions of dynamic histone acetylation.

Besides its role in organizing nuclear DNA, the nuclear matrix is involved in specific nuclear functions, including replication, transcription, and RNA splicing. It is becoming increasingly evident that nuclear processes are localized to distinct regions in the nucleus. For example, transcriptionally active genes and RNA transcripts are found in discrete transcription foci. Current evidence suggests that nuclear matrix-bound transcriptionally active DNA sequences are in nucleosomes with dynamically acetylated histones. Histone acetylation, which precedes transcription, alters nucleosome and chromatin structure, decondensing the chromatin fibre and making the nucleosomal DNA accessible to transcription factors. Histone acetyltransferase and histone deacetylase, which catalyze this rapid acetylation and deacetylation, are associated with the internal nuclear matrix. We hypothesize that these enzymes play a role in maintaining the association of the active chromatin domains with the internal nuclear matrix at sites of ongoing transcription.

Acetylation↗
PubMed2000

Significance of protein kinase CK2 nuclear signaling in neoplasia.

Many stimuli play a role in influencing the structure and function of chromatin and nuclear matrix through post-translational modifications of the component proteins in these dynamic structures. We propose that the protein serine/threonine kinase CK2 (formerly casein kinase II) is one such agent that is involved in signal transduction in the nuclear matrix and chromatin in response to a variety of stimuli. Protein kinase CK2 appears to undergo rapid modulations in its association with nuclear matrix and nucleosomes in response to mitogenic signals and is involved in the phosphorylation of a variety of intrinsic proteins in these structures depending on the state of genomic activity. In addition, its association or loss from the nuclear matrix may also influence the apoptotic activity in the cell. CK2 has been found to be dysregulated in virtually all the neoplasias examined and nuclear association appears to be an important facet of its expression in tumor cells. We hypothesize that CK2 provides a functional paradigm linking the nuclear matrix and chromatin structures. Identification of precise loci of action of CK2 in these structures and how they influence the morphological appearance of the nucleus under normal and abnormal growth conditions would be an important future direction of investigation. J. Cell. Biochem. Suppl. 35:130-135, 2000. Published 2001 Wiley-Liss, Inc.

Animals↗
PubMed2002

Cytoplasmic intermediate filaments are stably associated with nuclear matrices and potentially modulate their DNA-binding function.

The tight association of cytoplasmic intermediate filaments (cIFs) with the nucleus and the isolation of crosslinkage products of vimentin with genomic DNA fragments, including nuclear matrix attachment regions (MARs) from proliferating fibroblasts, point to a participation of cIFs in nuclear activities. To test the possibility that cIFs are complementary nuclear matrix elements, the nuclei of a series of cultured cells were subjected to the Li-diiodosalicylate (LIS) extraction protocol developed for the preparation of nuclear matrices and analyzed by immunofluorescence microscopy and immunoblotting with antibodies directed against lamin B and cIF proteins. When nuclei released from hypotonically swollen L929 suspension cells in the presence of digitonin or Triton X-100 were exposed to such strong shearing forces that a considerable number were totally disrupted, a thin, discontinuous layer of vimentin IFs remained tenaciously adhering to still intact nuclei, in apparent coalignment with the nuclear lamina. Even in broken nuclei, the distribution of vimentin followed that of lamin B in areas where the lamina still appeared intact. The same retention of vimentin together with desmin and glial IFs was observed on the nuclei isolated from differentiating C2C12 myoblast and U333 glioma cells, respectively. Nuclei from epithelial cells shed their residual perinuclear IF layers as coherent cytoskeletal ghosts, except for small fractions of vimentin and cytokeratin IFs, which remained in a dot-to cap-like arrangement on the nuclear surface, in apparent codistribution with lamin B. LIS extraction did not bring about a reduction in the cIF protein contents of such nuclei upon their transformation into nuclear matrices. Moreover, in whole mount preparations of mouse embryo fibroblasts, DNA/chromatin emerging from nuclei during LIS extraction mechanically and chemically cleaned the nuclear surface and perinuclear area from loosely anchored cytoplasmic material with the production of broad, IF-free annular spaces, but left substantial fractions of the vimentin IFs in tight association with the nuclear surface. Accordingly, double-immunogold electron microscopy of fixed and permeabilized fibroblasts disclosed a close neighborhood of vimentin IFs and lamin B, with a minimal distance between the nanogold particles of ca. 30 nm. These data indicate an extremely solid interconnection of cIFs with structural elements of the nuclear matrix, and make them, together with their susceptibility to crosslinkage to MARs and other genomic DNA sequences under native conditions, complementary or even integral constituents of the karyoskeleton.

Animals↗
PubMed1992

Intracellular histamine and liver regeneration: high affinity binding of histamine to chromatin, low affinity binding to matrix, and depletion of a nuclear storage pool following partial hepatectomy.

We have demonstrated in rat hepatocytes that 3H-histamine binds specifically to novel low (microM) and high (nM) affinity sites, designated "HIC" to denote their intracellular location. Low affinity HIC sites are associated with microsomes, while both low and high affinity HIC sites are associated with the nucleus. A growth-regulatory action of intracellular histamine at HIC, independent of the rise in cytosolic calcium, has been demonstrated in mitogen-stimulated lymphocytes. We now report that the high affinity HIC sites in liver cell nuclei are associated exclusively with chromatin, while only low affinity sites are found in the residual material containing the nuclear matrix. Moreover, hepatocyte nuclei contain histamine (approximately 1 ng/mg protein), unaffected by incubation for up to 18 hours with the histidine decarboxylase inhibitor, alpha-FMH, suggesting a slow rate of turnover typical of a storage pool. A decrease in nuclear histamine parallels a rise in DNA synthesis in the first 24 hours after partial hepatectomy. Our findings support a role for a nuclear pool of pre-formed histamine in the mediation of liver regeneration.

Animals↗
PubMed1982

On the localization and transport of specific adenoviral mRNA-sequences in the late infected HeLa cell.

In the nucleus of HeLa cells late after infection with adenovirus type 2 mRNA-sequences which are processed via RNA splicing are attached to the nuclear matrix (Mariman et al., 1982). Although the mRNA, which codes for polypeptide IX, is not formed via splicing, about 70% of the non-polyadenylated pre-mRNA and the polyadenylated pIX mRNA are bound to the matrix structure, indicating that polyadenylation is performed while the RNA is associated with the matrix. Binding to the nuclear matrix seems to be a common property of all mRNA-sequences in the nucleus. At the late stage of infection most of the newly synthesized mRNAs which appear in the cytoplasm are viral specific (Beltz & Flint, 1979). Kinetic analysis of the newly synthesized poly(A)-containing mRNA on sucrose gradients reveals that 7-12 S messengers appear more rapidly in the cytoplasm than messengers larger than 13 S. More specifically, the nuclear exit time of the pIX-mRNA, which is the major 9 S adenoviral messenger late after infection, was determined to be about 4 min, while messengers transcribed from the late region 3 need more than 16 min to arrive in the cytoplasm. In the cytoplasm about 70% of the mRNA is bound to the cytoskeletal framework, while 30% remains as free mRNP. Analysis of the mRNA in both fractions reveals that L3-, E1B- and pIX-specific polyadenylated mRNA preferably exist as cytoskeleton-bound mRNA. However, significant differences occur in the partition of specific messengers over free and cytoskeletal RNA fractions.

Adenoviruses, Human↗
PubMed2006

Fulvestrant (ICI 182,780)-dependent interacting proteins mediate immobilization and degradation of estrogen receptor-alpha.

The antiestrogen fulvestrant (ICI 182,780) causes immobilization of estrogen receptor-alpha (ERalpha) in the nuclear matrix accompanied by rapid degradation by the ubiquitin-proteasome pathway. In this study we tested the hypothesis that fulvestrant induces specific nuclear matrix protein-ERalpha interactions that mediate receptor immobilization and turnover. A glutathione S-transferase (GST)-ERalpha-activating function-2 (AF2) fusion protein was used to isolate and purify receptor-interacting proteins in cell lysates prepared from human MCF-7 breast cancer cells. After SDS-PAGE and gel excision, mass spectrometry was used to identify two major ERalpha-interacting proteins, cytokeratins 8 and 18 (CK8.CK18). We determined, using ERalpha-activating function-2 mutants, that helix 12 (H12) of ERalpha, but not its F domain, is essential for fulvestrant-induced ERalpha-CK8 and CK18 interactions. To investigate the in vivo role of H12 in fulvestrant-induced ERalpha immobilization/degradation, transient transfection assays were performed using wild type ERalpha,ERalpha with a mutated H12, and ERalpha with a deleted F domain. Of those, only the ERalpha H12 mutant was resistant to fulvestrant-induced immobilization to the nuclear matrix and protein degradation. Fulvestrant treatment caused ERalpha degradation in CK8.CK18-positive human breast cancer cells, and CK8 and CK18 depletion by small interference RNAs partially blocked fulvestrant-induced receptor degradation. Furthermore, fulvestrant-induced ERalpha degradation was not observed in CK8 or CK18-negative cancer cells, suggesting that these two intermediate filament proteins are necessary for fulvestrant-induced receptor turnover. Using an ERalpha-green fluorescent protein construct in fluorescence microscopy revealed that fulvestrant-induced cytoplasmic localization of newly synthesized receptor is mediated by its interaction with CK8 and CK18. In summary, this study provides the first direct evidence linking ERalpha immobilization and degradation to the nuclear matrix. We suggest that fulvestrant induces ERalpha to interact with CK8 and CK18, drawing the receptor into close proximity to nuclear matrix-associated proteasomes that facilitate ERalpha turnover.

Breast Neoplasms↗
PubMed1975

Nuclear protein matrix: association with newly synthesized DNA.

The residual structural framework of the cell nucleus termed the nuclear protein matrix, is associated with newly synthesized DNA in regenerating rat liver. One minute after rats are injected with [3-H] thymidine, more than 90 percent of the total tritium in nuclear DNA is associated with the matrix DNA although this DNA comprises only 25 percent of the total nuclear DNA. In contrast, the bulk DNA, 75 percent of total nuclear DNA, contains less than 8 percent of the total labeled DNA. The percentage of total labeled DNA associated with the bulk DNA increases for 30 minutes after injection and decreases correspondingly in the matrix DNA.

Animals↗
PubMed1985

In vitro interaction of 63-nickel(II) with chromatin and DNA from rat kidney and liver nuclei.

The interaction of nickel(II) with chromatin was studied in vitro and in isolated nuclei from rat liver and kidney. Nickel(II) bound to chromatin, polynucleosomes (DNA + histone octamer protein complex), and to deproteinized DNA both in intact nuclei and in vitro. The amount of nickel(II) bound depended on the concentration of nickel(II), the presence of chromosomal proteins and the binding sites on DNA which provide a stable coordination environment for nickel(II). The binding of nickel(II) to chromatin and to DNA in whole nuclei was much slower than in vitro indicating that assessibility of the DNA binding sites was influenced by the presence of the nuclear membrane, nuclear matrix and nuclear proteins and/or by the condensed nuclear structure of chromatin. Since DNA containing bound nickel(II) was isolated from chromatin, nickel(II) directly interacted with stable binding sites on the DNA molecule in chromatin. Nickel(II) was associated with the histone and non-histone nuclear proteins as well as the DNA in rat liver and kidney chromatin. Nickel(II) was found to bind to calf thymus histones in vitro. Nickel(II)-nuclear protein and -DNA interactions were investigated by gel electrophoretic analysis of in vitro incubation products. Although nickel-histone and nickel-non-histone protein interactions were completely disrupted by the electrophoretic conditions, fluorography revealed the presence of inert nickel(II)-DNA and/or nickel(II)-DNA-protein complexes.

Animals↗