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PubMed1999

Isolation and characterization of an oligomerization-negative mutant of HIV-1 integrase.

The yeast two-hybrid method was used to screen mutagenized DNAs to isolate a variant of the human immunodeficiency virus type 1 integrase (IN) that does not interact with the wild-type IN. The responsible mutation, leading to a single amino acid change (V260E) in the C-terminal domain of IN, blocks IN-IN multimerization but has only small effect on binding to a host interacting protein, INI1 (hSNF5). Binding studies in vitro confirmed the defect in multimerization of the mutant IN. Biochemical analyses of the mutant IN enzyme expressed in bacteria detected only subtle changes in its properties, suggesting that the yeast system is a sensitive reporter of correct IN conformation. Mutant virus carrying the V260E substitution was blocked in replication at the time of DNA integration, consistent with IN multimerization being important for its activity in vivo.

Amino Acid Sequence↗

PubMed2005

Complementation analyses suggest species-specific functions of the SNF5 homology domain.

Inactivation on both alleles of the hSNF5/INI1 tumor suppressor gene which encodes a subunit of the human SWI/SNF chromatin remodelling complex occurs in most malignant rhabdoid tumors. No paralog of hSNF5/INI1 is identified in the human genome. In contrast, it has two homologs in the yeast Saccharomyces cerevisiae, SNF5 and SFH1 which encode core components of the ySWI/SNF and RSC complexes, respectively. The homology mainly concerns an approximately 200 amino acid region termed the SNF5 homology domain. We have tested the ability of the hSNF5/INI1-wild type gene product and of chimerical constructs in which the yeast SNF5 domains were replaced by that of the human protein, to complement yeast snf5 and sfh1 phenotypes. Neither growth deficiencies on different carbon sources of snf5 yeasts nor the lethality of the sfh1 phenotype could be rescued. This strongly suggests that the SNF5 homology domain presents species-specific functions.

Amino Acid Sequence↗

PubMed2006

Cellular co-factors of HIV-1 integration.

To achieve productive infection, the reverse transcribed cDNA of human immunodeficiency virus type 1 (HIV-1) is inserted in the host cell genome. The main protein responsible for this reaction is the viral integrase. However, studies indicate that the virus is assisted by cellular proteins, or co-factors, to achieve integration into the infected cell. The barrier-to-autointegration factor (BAF) might prevent autointegration. Its ability to bridge DNA and the finding that the nuclear lamina-associated polypeptide-2alpha interacts with BAF suggest a role in nuclear structure organization. Integrase interactor 1 was found to directly interact with HIV-1 integrase and to activate its DNA-joining activity, and the high mobility group chromosomal protein A1 might approximate both long terminal repeat (LTR) ends and facilitate integrase binding by unwinding the LTR termini. Furthermore, the lens-epithelium-derived growth factor (LEDGF; also known as p75) seems to tether HIV-1 integrase to the chromosomes. Although a direct role in integration has only been demonstrated for LEDGF/p75, to date, each validated cellular co-factor for HIV-1 integration could constitute a promising new target for antiviral therapy.

Animals↗

PubMed2000

BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer.

Germline mutations in the tumor suppressor gene, BRCA1, predispose individuals to breast and ovarian cancers. Using a combination of affinity- and conventional chromatographic techniques, we have isolated a predominant form of a multiprotein BRCA1-containing complex from human cells displaying chromatin-remodeling activity. Mass spectrometric sequencing of components of this complex indicated that BRCA1 is associated with a SWI/SNF-related complex. We show that BRCA1 can directly interact with the BRG1 subunit of the SWI/SNF complex. Moreover, p53-mediated stimulation of transcription by BRCA1 was completely abrogated by either a dominant-negative mutant of BRG1 or the cancer-causing deletion in exon 11 of BRCA1. These findings reveal a direct function for BRCA1 in transcriptional control through modulation of chromatin structure.

BRCA1 Protein↗

PubMed1999

A role for transcriptional repressors in targeting the yeast Swi/Snf complex.

Genetic and biochemical studies indicate that the evolutionarily conserved Swi/Snf complex acts at a subset of genes to help transcriptional activators function on chromatin templates. The mechanism by which this complex is targeted to specific chromosomal loci remains unknown. We show that Swi/Snf is required for expression of the yeast histone HTA1-HTB1 locus because of the role of Hir1p and Hir2p corepressors in negatively regulating transcription. Snf5p, Snf2p/Swi2p, and Swi3p, three components of the yeast Swi/Snf complex, coimmunoprecipitate with each Hir protein, and Snf5p is maximally associated with the HTA1-HTB1 promoter when the Hir-based repression system is intact and the Swi/Snf complex is functional. The data support a role for the Hir repressors in the gene-specific targeting of Swi/Snf.

Adenosine Triphosphatases↗

PubMed1999

Interaction of E1 and hSNF5 proteins stimulates replication of human papillomavirus DNA.

Mammalian viruses often use components of the host's cellular DNA replication machinery to carry out replication of their genomes, which enables these viruses to be used as tools for characterizing factors that are involved in cellular DNA replication. The human papillomavirus (HPV) E1 protein is essential for replication of the virus DNA. Here we identify the cellular factor that participates in viral DNA replication by using a two-hybrid assay in the yeast Saccharomyces cerevisiae and E1 protein as bait. Using this assay, we isolated Inil/hSNF5, a component of the SWI/SNF complex which facilitates transcription by altering the structure of chromatin. In vitro binding and immunoprecipitation confirmed that E1 interacts directly with Ini1/hSNF5. Transient DNA-replication assay revealed that HPV DNA replication is stimulated in a dose-dependent manner by addition of Ini1/hSNF5, and that Ini1/hSNF5 antisense RNA blocks the replication of HPV DNA. Amino-acid substitution at residues that are conserved among E1 proteins prevented the E1-Ini1/hSNF5 interaction and reduced DNA replication of HPV in vivo. Our results indicate that Ini1/hSNF5 is required for the efficient replication of papillomavirus DNA and is therefore needed, either alone or in complex with SWI/SNF complex, for mammalian DNA replication as well.

Binding Sites↗

PubMed2000

ORC1 interacts with c-Myc to inhibit E-box-dependent transcription by abrogating c-Myc-SNF5/INI1 interaction.

BACKGROUND: The c-myc oncogene product (c-Myc) is a transcription factor that forms a complex with Max and recognizes the E-box sequence. c-Myc plays key functions in cell proliferation, differentiation and apoptosis. As for its activity towards cell proliferation, it is generally thought that c-Myc transactivates the E-box-containing genes that encode proteins essential to cell-cycle progression. Despite the characterization of candidate genes regulated by c-Myc in culture cells, these have still not been firmly recognized as real target genes for c-Myc. RESULTS: We found that c-Myc directly bound to the N-terminal region of origin recognition complex-1 (ORC1), a region that is responsible for gene silencing, in a state of complex containing other ORC subunits and Max in vivo and in vitro. Furthermore, ORC1 inhibited E-box-dependent transcription activity of c-Myc by competitive binding to the C-terminal region of c-Myc with SNF5, a component of chromatin remodelling complex SNF/Swi1. CONCLUSIONS: These results suggest that ORC1 suppresses the transcription activity of c-Myc by its recruitment into an inactive form of chromatin during some stage of the cell cycle.

Binding, Competitive↗

PubMed2000

Upstream nucleosomes and Rgr1p are required for nucleosomal repression of transcription.

The mechanisms of transcription repression and derepression in vivo are not fully understood. We have obtained evidence that begins to clarify the minimum requirements for counteracting nucleosomal repression in vivo. Location of the TATA element near the nucleosome dyad does not block RNA polymerase II transcription in vivo if there is a nucleosome-free region located immediately upstream. However, location of the TATA element similarly within the nucleosome does block transcription if the region upstream of it is nucleosome bound. Histone H4 depletion derepresses transcription in the latter case, supporting the idea that the nucleosomes are responsible for the repression. These results raise the intriguing possibility that the minimum requirement for derepression of transcription in vivo is a nucleosome-free region upstream of the core promoter. Importantly, we find that a C-terminal deletion in RGR1, a component of the mediator/holoenzyme complex and a global repressor, can also derepress transcription.

Chromosomal Proteins, Non-Histone↗

PubMed1994

A multisubunit complex containing the SWI1/ADR6, SWI2/SNF2, SWI3, SNF5, and SNF6 gene products isolated from yeast.

A complex containing the products of the SWI1/ADR6, SWI2/SNF2, SWI3, SNF5, and SNF6 genes and four additional polypeptides has been purified from extracts of the yeast Saccharomyces cerevisiae. Physical association of these proteins was demonstrated by copurification and coimmunoprecipitation. A potent DNA-dependent ATPase copurified with the complex, and this activity was evidently associated with SWI2/SNF2.

Adenosine Triphosphatases↗

PubMed1998

The C-terminal SET domains of ALL-1 and TRITHORAX interact with the INI1 and SNR1 proteins, components of the SWI/SNF complex.

The ALL-1 gene was discovered by virtue of its involvement in human acute leukemia. Its Drosophila homolog trithorax (trx) is a member of the trx-Polycomb gene family, which maintains correct spatial expression of the Antennapedia and bithorax complexes during embryogenesis. The C-terminal SET domain of ALL-1 and TRITHORAX (TRX) is a 150-aa motif, highly conserved during evolution. We performed yeast two hybrid screening of Drosophila cDNA library and detected interaction between a TRX polypeptide spanning SET and the SNR1 protein. SNR1 is a product of snr1, which is classified as a trx group gene. We found parallel interaction in yeast between the SET domain of ALL-1 and the human homolog of SNR1, INI1 (hSNF5). These results were confirmed by in vitro binding studies and by demonstrating coimmunoprecipitation of the proteins from cultured cells and/or transgenic flies. Epitope-tagged SNR1 was detected at discrete sites on larval salivary gland polytene chromosomes, and these sites colocalized with around one-half of TRX binding sites. Because SNR1 and INI1 are constituents of the SWI/SNF complex, which acts to remodel chromatin and consequently to activate transcription, the interactions we observed suggest a mechanism by which the SWI/SNF complex is recruited to ALL-1/trx targets through physical interactions between the C-terminal domains of ALL-1 and TRX and INI1/SNR1.

Amino Acid Sequence↗

PubMed2002

SWI/SNF complex interacts with tumor suppressor p53 and is necessary for the activation of p53-mediated transcription.

The SWI/SNF complex is required for the transcription of several genes and has been shown to alter nucleosome structure in an ATP-dependent manner. The tumor suppressor protein p53 displays growth and transformation suppression functions that are frequently lost in mutant p53 proteins detected in various cancers. Using genetic and biochemical approaches, we show that several subunits of the human SWI/SNF complex bind to the tumor suppressor protein p53 in vivo and in vitro. The transactivation function of p53 is stimulated by overexpression of hSNF5 and BRG-1 and dominant forms of hSNF5 and BRG-1 repress p53-dependent transcription. Chromatin immunoprecipitation assay shows that hSNF5 and BRG-1 are recruited to a p53-dependent promoter in vivo. Overexpression of dominant negative forms of either hSNF5 or BRG-1 inhibited p53-mediated cell growth suppression and apoptosis. Molecular connection between p53 and the SWI/SNF complex implicates that (i) the SWI/SNF complex is necessary for p53-driven transcriptional activation, and (ii) the SWI/SNF complex plays an important role in p53-mediated cell cycle control.

Adenosine Triphosphatases↗

PubMed2002

The human SNF5/INI1 protein facilitates the function of the growth arrest and DNA damage-inducible protein (GADD34) and modulates GADD34-bound protein phosphatase-1 activity.

The growth arrest and DNA damage-inducible protein (GADD34) mediates growth arrest and apoptosis in response to DNA damage, negative growth signals, and protein malfolding. GADD34 binds to protein phosphatase-1 (PP1) and can attenuate translational elongation of key transcriptional factors through dephosphorylation of eukaryotic initiation factor-2alpha. We reported previously that the human trithorax leukemia fusion protein (HRX) can bind to GADD34 and abrogate GADD34-mediated apoptosis in response to UV irradiation. We found that hSNF5/INI1, a component of the hSWI/SNF chromatin remodeling complex, also binds to GADD34 and can coexist with GADD34 and HRX fusion proteins as a trimolecular complexes in vivo. In the present report, we demonstrate that hSNF5/INI1 binds to GADD34 in part through the PP1 docking site within a domain homologous to herpes simplex virus-1 ICP34.5. We found that hSNF5/INI1 can bind PP1 independently and weakly stimulate its phosphatase activity in solution and in complex with GADD34. hSNF5/INI1 and PP1 do not compete for binding to GADD34 but rather form a stable heterotrimeric complex with GADD34. We also show that Epstein-Barr nuclear protein 2, which binds hSNF5/INI1, can disrupt hSNF5/INI1 binding to GADD34 and partially reverse the GADD34-mediated growth suppression function in Ha-ras expressing HIH-3T3 (3T3-ras) cells. These results implicate hSNF5/INI1 in the function of GADD34 and suggest that hSNF5/INI1 may regulate PP1 activity in vivo.

3T3 Cells↗

PubMed1998

The yeast protein complex containing cdc68 and pob3 mediates core-promoter repression through the cdc68 N-terminal domain.

Transcription of nuclear genes usually involves trans-activators, whereas repression is exerted by chromatin. For several genes the transcription mediated by trans-activators and the repression mediated by chromatin depend on the CP complex, a recently described abundant yeast nuclear complex of the Pob3 and Cdc68/Spt16 proteins. We report that the N-terminal third of the Saccharomyces cerevisiae Cdc68 protein is dispensable for gene activation but necessary for the maintenance of chromatin repression. The absence of this 300-residue N-terminal domain also decreases the need for the Swi/Snf chromatin-remodeling complex in transcription and confers an Spt- effect characteristic of chromatin alterations. The repression domain, and indeed the entire Cdc68 protein, is highly conserved, as shown by the sequence of the Cdc68 functional homolog from the yeast Kluyveromyces lactis and by database searches. The repression-defective (truncated) form of Cdc68 is stable but less active at high temperatures, whereas the known point-mutant form of Cdc68, encoded by three independent mutant alleles, alters the N-terminal repression domain and destabilizes the mutant protein.

Adenosine Triphosphatases↗

PubMed2006

Mouse MAELSTROM: the link between meiotic silencing of unsynapsed chromatin and microRNA pathway?

Meiotic silencing of unsynapsed chromatin (MSUC) is a key mechanism in spermatogenesis and a model system to study the dynamics of gene silencing. Here we show that MAEL, the ortholog of Drosophila's high mobility group box protein Maelstrom, is associated not only with the silenced XY body, but also with unsynapsed autosomes. Characterization of MAEL revealed that it interacts directly with the chromatin remodeler SNF5/INI1 and chromatin-associated protein SIN3B, which we also find localized to the XY body. This is the first time that a chromatin remodeler has been shown to associate with whole chromosomes. In addition, we show that MAEL is a component of the mouse meiotic nuage and its haploid cell counterpart, the chromatoid body. This is a site of accumulation of RNA and RNA processing enzymes, including proteins involved in the microRNA (miRNA) pathway. Furthermore, in the nuage, MAEL is present in a complex with germ cell specific MVH, an RNA helicase and Argonaute family members, MILI and MIWI. The presence of MAEL in these critical compartments of male germ cells and its interactions provide a link suggesting the involvement of the miRNA pathway in MSUC.

Animals↗

PubMed2002

AtSWI3B, an Arabidopsis homolog of SWI3, a core subunit of yeast Swi/Snf chromatin remodeling complex, interacts with FCA, a regulator of flowering time.

ATP-dependent nucleosome remodeling plays a central role in the regulation of access to chromatin DNA. Swi/Snf remodeling complexes characterized in yeast, Drosophila and mammals all contain a conserved set of core subunits composed of homologs of yeast SNF2-type DNA-dependent ATPase, SNF5 and SWI3 proteins. So far, no complete Swi/Snf-type complex has been characterized in plants. Arabidopsis contains a single SNF5-type gene, BSH, which has been shown to complement the yeast snf5 mutation. Here we describe the characterization of AtSWI3B, the smallest of the four Arabidopsis homologs of SWI3. The gene encoding AtSWI3B is expressed ubiquitously in the plant. AtSWI3B is localized to nuclei and is associated mostly with the chromatin and soluble protein fractions. When expressed in Saccharomyces cerevisiae, the cDNA encoding AtSWI3B partially complements the swi3 mutant phenotype. However, like BSH, AtSWI3B is unable to activate transcription in yeast when tethered to DNA. The analysis by yeast two-hybrid indicates that AtSWI3B is capable of forming homodimers and interacts with BSH as well as with two other members of the Arabidopsis SWI3 family: AtSWI3A and AtSWI3C. The results of phage display screen using recombinant protein, confirmed by direct yeast two-hybrid analyses, indicate that AtSWI3B interacts with FCA, a regulator of flowering time in Arabidopsis. This interaction is through the C-terminal region of FCA, located outside the conserved RNA- and protein-binding domains of this protein.

Amino Acid Sequence↗

PubMed2003

Kaposi's sarcoma-associated herpesvirus K8 protein interacts with hSNF5.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus related to Epstein-Barr virus (EBV) and herpesvirus saimiri. KSHV open reading frame K8 encodes a basic region-leucine zipper protein of 237 aa that homodimerizes. K8 shows significant similarity to the EBV immediate-early protein Zta, a key regulator of EBV reactivation and replication. In this study, a carboxyl-terminal deletion mutant of K8, K8(1-115), that had strong transactivating properties was found. Screening using transcriptionally inactive K8(1-75) showed that K8 interacts and co-localizes with hSNF5, a cellular chromatin-remodelling factor, both in vivo and in vitro. This interaction requires aa 48-183 of hSNF5 and 1-75 of K8. In a yeast expression system, the ability of K8 and K8(1-115) to activate transcription requires the presence of SNF5, the yeast homologue of hSNF5. These data suggest a mechanism by which the SWI-SNF complex is recruited to specific genes. They also suggest that K8 functions as a transcriptional activator under specific conditions and that its transactivation activity requires its interaction with the cellular chromatin remodelling factor hSNF5.

Basic-Leucine Zipper Transcription Factors↗

PubMed2002

Evidence that Swi/Snf directly represses transcription in S. cerevisiae.

Many studies have established that the Swi/Snf family of chromatin-remodeling complexes activate transcription. Recent reports have suggested the possibility that these complexes can also repress transcription. We now present chromatin immunoprecipitation evidence that the Swi/Snf complex of Saccharomyces cerevisiae directly represses transcription of the SER3 gene. Consistent with its role in nucleosome remodeling, Swi/Snf controls the chromatin structure of the SER3 promoter. However, in striking contrast to activation by Swi/Snf, which requires most Swi/Snf subunits, repression by Swi/Snf at SER3 is dependent primarily on one Swi/Snf component, Snf2. These results show distinct differences in the requirements for Swi/Snf components in transcriptional activation and repression.

Adenosine Triphosphatases↗

PubMed1992

Evidence that SNF2/SWI2 and SNF5 activate transcription in yeast by altering chromatin structure.

Changes in chromatin structure have frequently been correlated with changes in transcription. However, the cause-and-effect relationship between chromatin structure and transcription has been hard to determine. In addition, identifying the proteins that regulate chromatin structure has been difficult. Recent evidence suggests that a functionally related set of yeast transcriptional activators (SNF2/SWI2, SNF5, SNF6, SWI1, and SWI3), required for transcription of a diverse set of genes, may affect chromatin structure. We now present genetic and molecular evidence that at least two of these transcriptional activators, SNF2/SWI2 and SNF5, function by antagonizing repression mediated by nucleosomes. First, the transcriptional defects in strains lacking these SNF genes are suppressed by a deletion of one of the two sets of genes encoding histones H2A and H2B, (hta1-htb1) delta. Second, at one affected promoter (SUC2), chromatin structure is altered in snf2/swi2 and snf5 mutants, and this chromatin defect is suppressed by (hta1-htb1) delta. Finally, analysis of chromatin structure at a mutant SUC2 promoter, in which the TATA box has been destroyed, demonstrates that the differences in SUC2 chromatin structure between SNF5+ and snf5 mutant strains are not simply an effect of different levels of SUC2 transcription. Thus, these results strongly suggest that SNF2/SWI2 and SNF5 cause changes in chromatin structure and that these changes allow transcriptional activation.

Adenosine Triphosphatases↗