Snf5-related 1


Mammalian SNF5 homologs

Several eukaryotic multiprotein complexes, including the Saccharomyces cerevisiae Snf/Swi complex, remodel chromatin for transcription. In contrast to the Snf/Swi proteins, Sfh1p, a new Snf5p paralog, is essential for viability. The evolutionarily conserved domain of Sfh1p is sufficient for normal function, and Sfh1p interacts functionally and physically with an essential Snf2p paralog in a novel nucleosome-restructuring complex called RSC (for remodels the structure of chromatin). A temperature-sensitive sfh1 allele arrests cells in the G2/M phase of the cell cycle, and the Sfh1 protein is specifically phosphorylated in the G1 phase. Together, these results demonstrate a link between chromatin remodeling and progression through the cell division cycle, providing genetic clues to possible targets for RSC function (Cao, 1997).

Distinct complexes of nine to 12 proteins (referred to as BRG1-associated factors [BAFs]) have been purified from several mammalian cell lines using an antibody to the SWI2-SNF2 homolog BRG1. Microsequencing reveals that the 47 kDa BAF is identical to INI1. Previously, INI1 has been shown to interact with and activate human immunodeficiency virus integrase and to be homologous to the yeast SNF5 gene. A group of BAF47-associated proteins were affinity purified with antibodies against INI1/BAF47 and were found to be identical to those co-purified with BRG1, strongly indicating that this group of proteins associates tightly and is likely to be the mammalian equivalent of the yeast SWI-SNF complex. Complexes containing BRG1 can disrupt nucleosomes and facilitate the binding of GAL4-VP16 to a nucleosomal template similar to the yeast SWI-SNF complex. Purification of the complex from several cell lines demonstrates that it is heterogeneous with respect to subunit composition. The two SWI-SNF2 homologs, BRG1 and hbrm, are found in separate complexes. Certain cell lines completely lack BRG1 and hbrm, indicating that they are not essential for cell viability and that the mammalian SWI-SNF complex may be tailored to the needs of a differentiated cell type (Wang, 1996).

Protein complexes of the SWI/SNF family remodel nucleosome structure in an ATP-dependent manner. Each complex contains between 8 and 15 subunits, several of which are highly conserved between yeast, Drosophila, and humans. An ATP-dependent chromatin remodeling complex has been reconstituted using a subset of conserved subunits. Unexpectedly, both BRG1 and hBRM, the ATPase subunits of human SWI/SNF complexes, are capable of remodeling mono-nucleosomes and nucleosomal arrays as purified proteins. The addition of INI1, BAF155, and BAF170 to BRG1 increases remodeling activity to a level comparable to that of the whole hSWI/SNF complex. These data define the functional core of the hSWI/SNF complex (Phelan, 1999).

Retroviral integrase (IN) catalyzes the integration of retroviral cDNA into host chromosome. Ini1 (integrase interactor 1) is a host protein that specifically binds and stimulates the in vitro joining activity of HIV-1 IN. Ini1 has homology to yeast transcription factor SNF5 and is a component of the analogous mammalian SWI/SNF complex that can remodel chromatin. Little is known about the function of Ini1 in mammalian cells. To gain insight into the functional domains of Ini1, and to understand the details of protein-protein interactions of IN and Ini1, a structure-function analysis of Ini1 was initiated. One of three conserved regions of Ini1 is necessary and sufficient for interaction with IN, indicating that at least one of these regions is a protein-protein interaction motif. By means of the yeast two-hybrid system, the minimal IN binding domain of Ini1 was characterized. One of the two repeat motifs present in the highly conserved regions of Ini1 was found necessary and sufficient to bind to IN in yeast as well as in vitro. Because IN binds to only one of the two repeat motifs in this conserved region of Ini1, it appears that the IN-Ini1 interaction is very specific and functionally significant. Characterization of the DNA-binding properties of Ini1 reveals that Ini1 can bind to plasmid DNA, binding more readily to supercoiled DNA than to the relaxed circular DNA. The minimal domain for DNA binding was localized to a region upstream of repeat 1. The DNA binding activity of Ini1 is not required for its ability to interact with IN. The finding that the two repeat motifs of Ini1 display differential binding to HIV-1 IN and that this discrete component of mammalian SWI/SNF complex binds to DNA will help clarify the role of Ini1 in HIV-1 integration and in cellular process (Morozov, 1998).

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. In this paper the cellular factor that participates in viral DNA replication is identified by using a two-hybrid assay in the yeast Saccharomyces cerevisiae, with E1 protein as bait. Using this assay, Inil/hSNF5, a component of the SWI/SNF complex that facilitates transcription by altering the structure of chromatin, was isolated. In vitro binding and immunoprecipitation confirms 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 prevents the E1-Ini1/hSNF5 interaction and reduces DNA replication of HPV in vivo. These 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 (Lee, 1999).

Chromatin organization plays a key role in the regulation of gene expression. The evolutionarily conserved SWI/SNF complex is one of several multiprotein complexes that activate transcription by remodeling chromatin in an ATP-dependent manner. SWI2/SNF2 is an ATPase whose homologs, BRG1 and hBRM, mediate cell-cycle arrest; the SNF5 homolog, INI1/hSNF5, appears to be a tumor suppressor. A search for INI1-interacting proteins using the two-hybrid system led to the isolation of c-MYC, a transactivator. The c-MYC-INI1 interaction has been observed both in vitro and in vivo. The c-MYC basic helix-loop-helix (bHLH) and leucine zipper (Zip) domains and the INI1 repeat 1 (Rpt1) region are required for this interaction. c-MYC-mediated transactivation is inhibited by a deletion fragment of INI1 and the ATPase mutant of BRG1/hSNF2 in a dominant-negative manner contingent upon the presence of the c-MYC bHLH-Zip domain. These results suggest that the SWI/SNF complex is necessary for c-MYC-mediated transactivation and that the c-MYC-INI1 interaction helps recruit the complex. Recruitment of the SWI/SNF complex, mediated by the interaction of INI1 with c-MYC, may facilitate the transcription of a discrete subset of c-MYC target genes, especially those involved in apoptosis, which might explain the tumor-suppressor activity of INI1 (Cheng, 1999).

Gene activation in eukaryotes requires chromatin remodeling complexes like Swi/Snf and histone acetylases like SAGA. How these factors are recruited to promoters is not yet understood. Using surface plasmon resonance technology (CHIP), recruitment of Swi/Snf, SAGA, the repressor Ash1p, and transcription factors Swi5p and the cell cycle-regulatory transcription factor SBF were all measured to the HO endonuclease promoter as cells progressed through the yeast cell cycle. Swi5p's entry into nuclei at the end of anaphase recruits Swi/Snf, which then recruits SAGA. These two factors then facilitate SBF's binding. Ash1p, which only accumulates in daughter cell nuclei, binds to HO soon after Swi5p and aborts recruitment of Swi/Snf, SAGA, and SBF. Swi5p remains at HO for only 5 min. Swi/Snf's and SAGA's subsequent persistence at HO is self sustaining and constitutes an 'epigenetic memory' of HO's transient interaction with Swi5p (Cosma, 1999).

Malignant rhabdoid tumours (MRTs) are extremely aggressive cancers of early childhood. They can occur in various locations, mainly the kidney, brain and soft tissues. Cytogenetic and molecular analyses have shown that the deletion of region 11.2 of the long arm of chromosome 22 (22q11.2) is a recurrent genetic characteristic of MRTs, indicating that this locus may encode a tumour suppressor gene. The most frequently deleted part of chromosome 22q11.2 was mapped from a panel of 13 MRT cell lines. Six homozygous deletions were observed that delineate the smallest region of overlap between the cell lines. This region is found in the hSNF5/INI1 gene, which encodes a member of the chromatin-remodelling SWI/SNF multiprotein complexes. The sequence of hSNF5/INI1 was analyzed and frameshift or nonsense mutations of this gene were found in six other cell lines. These truncating mutations of one allele are associated with the loss of the other allele. Identical alterations are observed in corresponding primary tumour DNAs but not in matched constitutional DNAs, indicating that they had been acquired somatically. The observation of bi-allelic alterations of hSNF5/INI1 in MRTs suggests that loss-of-function mutations of hSNF5/INI1 contribute to oncogenesis (Versteege, 1998).

Eighteen atypical teratoid and rhabdoid tumors of the brain and 7 renal and 4 extrarenal rhabdoid tumors were examined for mutations in the candidate rhabdoid tumor suppressor gene, INI1. Fifteen tumors had homozygous deletions of one or more exons of the INI1 gene, and the other 14 tumors demonstrated mutations. Germ-line mutations of INI1 were identified in four children, one with an atypical teratoid tumor of the brain and three with renal rhabdoid tumors. These studies suggest that INI1 is a tumor suppressor gene involved in rhabdoid tumors of the brain, kidney, and other extrarenal sites (Biegel, 1999).

The assembly of eukaryotic DNA into nucleosomes and derived higher order structures constitutes a barrier for transcription, replication and repair. A number of chromatin remodeling complexes, as well as histone acetylation, have been shown to facilitate gene activation. To investigate the function of two closely related mammalian SWI/SNF complexes in vivo, the murine SNF5/INI1 gene, a common subunit of these two complexes, was inactivated. Mice lacking SNF5 protein stop developing at the peri-implantation stage, showing that the SWI/SNF complex is essential for early development and viability of early embryonic cells. Furthermore, heterozygous mice develop nervous system and soft tissue sarcomas. In these tumors the wild-type allele was lost, providing further evidence that SNF5 functions as a tumor suppressor gene in certain cell types (Klochendler-Yeivin, 2000).

The hSNF5/INI1 gene that encodes a member of the SWI/SNF chromatin ATP-dependent remodeling complex, is a tumor suppressor gene localized on chromosome 22q11.2 and is mutated in malignant rhabdoid tumors. hSNF5/INI1 mutations have been sought in 229 tumors of various origins using a screening method based on denaturing high-performance liquid chromatography. A total of 31 homozygous deletions and 36 point alterations were identified. Point mutations were scattered along the coding sequence and included 15 nonsense, 15 frameshift, three splice site, two missense and one editing mutations. Mutations were retrieved in most rhabdoid tumors, whatever their sites of occurrence, indicating the common pathogenetic origin of these tumors. Recurrent hSNF5/INI1 alterations were also observed in choroid plexus carcinomas and in a subset of central primitive neuroectodermal tumors (cPNETs) and medulloblastomas. In contrast, hSNF5/INI1 point mutations are not detected in breast cancers, Wilms' tumors, gliomas, ependymomas, sarcomas and other tumor types, even though most analyzed cases harbored loss of heterozygosity at 22q11.2 loci. These results suggest that rhabdoid tumors, choroid plexus carcinomas and a subset of medulloblastomas and cPNETs share common pathways of oncogenesis related to hSNF5/INI1 alteration and that hSNF5/INI1 mutations define a genetically homogeneous family of highly aggressive cancers mainly occurring in young children and frequently, but not always, exhibiting a rhabdoid phenotype (Sevenet, 1999).

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. c-Myc has been found to directly bind 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 inhibits 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. 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 (Takayama, 2000).

INI1/hSNF5 is a component of the ATP-dependent chromatin remodeling hSWI/SNF complex and a tumor suppressor gene of aggressive pediatric atypical teratoid and malignant rhabdoid tumors (AT/RT). To understand the molecular mechanisms underlying its tumor suppressor function, the effect has been studied of reintroduction of INI1/hSNF5 into AT/RT-derived cell lines such as MON that carry biallelic deletions of the INI1/hSNF5 locus. Expression of INI1/hSNF5 causes G(0)-G(1) arrest and flat cell formation in these cells. In addition, INI1/hSNF5 represses transcription of cyclin D1 gene in MON, in a histone deacetylase (HDAC)-dependent manner. Chromatin immunoprecipitation studies reveal that INI1/hSNF5 is directly recruited to the cyclin D1 promoter and that its binding correlates with recruitment of HDAC1 and deacetylation of histones at the promoter. Analysis of INI1/hSNF5 truncations indicates that cyclin D1 repression and flat cell formation are tightly correlated. Coexpression of cyclin D1 from a heterologous promoter in MON is sufficient to eliminate the INI1-mediated flat cell formation and cell cycle arrest. Furthermore, cyclin D1 was overexpressed in AT/RT tumors. These data suggest that one of the mechanisms by which INI1/hSNF5 exerts its tumor suppressor function is by mediating the cell cycle arrest due to the direct recruitment of HDAC activity to the cyclin D1 promoter thereby causing its repression and G(0)-G(1) arrest. Repression of cyclin D1 gene expression may serve as a useful strategy to treat AT/RT (Zhang, 2002).

The hSNF5/INI1 gene encodes a member of the SWI/SNF chromatin remodelling complexes. The gene has been identified as a tumour suppressor gene mutated in sporadic and hereditary Malignant Rhabdoid Tumours (MRT). However, the role of hSNF5/INI1 loss-of-function in tumour development is still unknown. This study shows that the ectopic expression of wild-type hSNF5/INI1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into S phase of MRT cells. This G1 arrest is associated with down-regulation of a subset of E2F targets, including cyclin A, E2F1 and CDC6. This arrest can be reverted by coexpression of cyclin D1, cyclin E or viral E1A, whereas it cannot be counteracted by pRB-binding deficient E1A mutants. Moreover, hSNF5/INI1 is not able to arrest cells lacking a functional pRB. These observations suggest that the hSNF5/INI1-induced G1 arrest is dependent upon the presence of a functional pRB. However, the observation that a constitutively active pRB can efficiently arrest MRT cells indicates that hSNF5/INI1 is dispensable for pRB function. Altogether, these data show that hSNF5/INI1 is a potent regulator of the entry into S phase, an effect that may account for its tumour suppressor role (Versteege, 2002).

Ini1/hsnf5 gene encodes INI1 protein, a chromatin remodeling factor associated with the SWI/SNF complex. In yeast, this complex modifies chromatin condensation to coactivate various transcriptional factors. However, in human, little is known about the SWI/SNF complex and INI1. To elucidate cellular functions of ini1, a recombinant adenovirus (AdexHA-INI1) was constructed capable of overexpressing INI1 in ini1-deficient cells. AdexHA-INI1 produced intranuclear INI1 in three ini1-deficient cell lines, changed their morphology, and decreased the proportion of viable cells. Flow cytometry and a BrdU incorporation assay showed that after the infection, growth of these cells was partially arrested at G1. In two of the three ini1-deficient cell lines, apoptosis was found to occur after the infection, as detected by the presence of cleaved poly (ADP-ribose) polymerase. To determine functional domains of INI1, plasmids were constructed expressing INI1 and its deletion mutants; these were examined using for a colony formation assay. Repeats 1 and 2 of INI1 were found to be required to suppress the growth of the three ini1-deficient cell lines. The results support the hypothesis that ini1 is a tumor suppressor gene and suggest a novel link between human SWI/SNF chromatin remodeling complex and apoptosis (Ae, 2002).

The SWI/SNF complex is required for the expression of many yeast genes. Previous studies have implicated DNA binding transcription activators in targeting SWI/SNF to UASs and promoters. To determine how activators interact with the complex and to examine the importance of these interactions, relative to other potential targeting mechanisms, for SWI/SNF function, attempts were made to identify and mutate the activator-interaction domains in the complex. The N-terminal domain of Snf5 and the second quarter of Swi1 are shown to be sites of activation domain contact. Deletion of both of these domains leaves the SWI/SNF complex intact but impairs its ability to bind activation domains. Importantly, while deletion of either domain alone has minor phenotypic effect, deletion of both result in strong SWI/SNF related phenotypes. Thus, two distinct activator-interaction domains play overlapping roles in the targeting activity of SWI/SNF, which is essential for its function in vivo (Prochasson, 2003).

The INI1 gene is often mutated or deleted in malignant rhabdoid tumor (MRT). Two isoforms of INI1, that differ by the variable inclusion of nine amino acids, potentially are produced by differential RNA splicing. To determine the effect of the two INI1 isoforms on cell growth, INI1-devoid (MRT) and INI1-expressing cell lines were transfected separately with mammalian expression vectors or transduced with adenoviruses. Transfection of the short form of INI1 into either INI1-deficient or expressing cell lines results in complete suppression of cell growth in colony formation assays. The longer splice variant induced moderate to severe growth suppression of MRT cells, but had a far milder effect on non-MRT cells. Transduction of MRT cells with adenoviruses expressing either isoform of INI1 led to a dramatic change in morphology, growth suppression, and cell cycle arrest. Furthermore, senescence-associated proteins were up-regulated after transduction, while levels of proteins implicated in cell cycle progression were down-regulated. Adenoviral delivery of INI1 into a non-MRT cell line, however, had no demonstrable effect on any of these parameters. These results support the genetic evidence that INI1 is a tumor suppressor gene gone awry in MRT cells, and also suggest that delivery of the INI1 gene to MRT cells by adenoviruses may lead to a more effective treatment of this highly aggressive malignancy (Reincke, 2003).

Targeting of specific promoters by the SWI/SNF complex

Ets-2 is a transcriptional activator that can be modulated by ras-dependent phosphorylation. Evidence is presented indicating that ets-2 can also act as a transcriptional repressor. In the breast cancer cell line MCF-7, exogenous ets-2 repressed the activity of a BRCA1 promoter-luciferase reporter dependent on a conserved ets-2-binding site in this promoter. Conditional overproduction of ets-2 in MCF-7 cells resulted in repression of endogenous BRCA1 mRNA expression. To address the mechanism by which ets-2 could act as a repressor, a biochemical approach was used to identify proteins that interacted with the ets-2 pointed domain. From this analysis, components of the mammalian SWI/SNF chromatin remodeling complex were found to interact with ets-2. Brg-1, the ATP-hydrolyzing component of the SWI/SNF complex, along with the BAF57/p50 and Ini1 subunits could be co-immunoprecipitated from cells with ets-2. The pointed domain of ets-2 directly interacts in vitro with the C-terminal region of Brg-1 in a phosphorylation-dependent manner. The combination of Brg-1 and ets-2 could repress the BRCA1 promoter reporter in transfection assays. These results support a role for ets-2 as a repressor and indicate that components of the mammalian SNF/SWI complex are required as co-repressors (Baker, 2003).

The hSNF5 subunit of human SWI/SNF ATP-dependent chromatin remodeling complexes is a tumor suppressor that is inactivated in malignant rhabdoid tumors (MRTs). Loss of hSNF5 function in MRT-derived cells leads to polyploidization and chromosomal instability. Re-expression of hSNF5 restores the coupling between cell cycle progression and ploidy checkpoints. In contrast, cancer-associated hSNF5 mutants harboring specific single amino acid substitutions exacerbate poly- and aneu-ploidization, due to abrogated chromosome segregation. It was found that hSNF5 activates the mitotic checkpoint through the p16INK4a-cyclinD/CDK4-pRb-E2F pathway. These results establish that polyploidy and aneuploidy of tumor cells can result from mutations in a chromatin remodeler (Vries, 2005).

General information about the SWI/SNF complex

To investigate the mechanism of SWI/SNF action, the pathway by which SWI/SNF stimulates formation of transcription factor-bound nucleosome core complexes has been analyzed. The SWI/SNF complex binds directly to nucleosome cores and uses the energy of ATP hydrolysis to disrupt histone/DNA interactions, altering the preferred path of DNA bending around the histone octamer. This disruption occurs without dissociating the DNA from the surface of the histone octamer. ATP-dependent disruption of nucleosomal DNA by SWI/SNF generates an altered nucleosome core conformation that can persist for an extended period after detachment of the SWI/SNF complex. This disrupted conformation retains an enhanced affinity for the transcription factor GAL4-AH. Thus, ATP-dependent nucleosome core disruption and enhanced binding of the transcription factor can be temporally separated. These results indicate that SWI/SNF can act transiently in the remodeling of chromatin structure, even before interactions of transcription factors (Cote, 1998).

Rotational phasing of DNA sequences on nucleosome cores is thought to largely result from intrinsic curvatures or anisotrophic flexibility of DNA sequences, which enhances the affinity of DNA sequences for histone octamers. Thus, the action of SWI/SNF in stimulating transcription factor binding might be explained by the complex reducing of the curvature of DNA sequences around the nucleosome core, thereby, reducing the strength of DNA interactions with the histone octamer and enhancing the affinity of DNA sites for transcription factors. Such a model is consistent with the observation that the human SWI/SNF complex reduces the number of stable supercoils in nucleosome-assembled plasmid DNA and is likely related to the DNA binding properties of SWI/SNF, which resemble those of high mobility group-box proteins and are capable of inducing positive supercoils in naked DNA (in the presence of Escherichia coli topoisomerase I). A similar interaction of SWI/SNF with nucleosomal DNA might require the energy of ATP hydrolysis to effect an allosteric change in nucleosome core structure. Importantly, this does not seem to involve a helicase activity of the SWI/SNF complex. The purified SWI/SNF complex does not appear to contain helicase activity; single-stranded regions are not detectable in SWI/SNF disrupted nucleosome cores (Cote, 1998 and references).

The continued accumulation of mechanistic data prompts a revision of a previously proposed model for SWI/SNF disruption of nucleosome cores and stimulation of activator binding. Earlier it was suggested that SWI/SNF action might provoke the loss of one or two H2A/H2B dimers from the core particle, stabilizing Gal4-AH-nucleosome core interaction. However, the data presented here showing the reversibility of the disrupted nucleosome core conformation argues against a loss of histone components during SWI/SNF disruption. These data suggest that SWI/SNF disrupts nucleosome cores primarily by perturbing histone/DNA interactions altering the path of the DNA around the core particle, without the eviction of histones. In addition to SWI/SNF disruption, actual displacement of histones appears to require further nucleosome core destabilization, as provided by the binding of multiple GAL4-AH dimers (Cote, 1998).

The size and subunit complexity of the SWI/SNF complex suggest that it may perform multiple functions and that its in vivo activity may differ in important details from the activities observed in vitro thus far. For example, the mechanisms by which the SWI/SNF complex might be targeted to specific chromosomal loci remains a topic of intense interest. Likely candidates for involvement in targeting of the complex includes interactions that have been detected between the SWI/SNF complex and holo-RNA polymerase, the glucocorticoid receptor, the retinoblastoma protein, and HIV-1 integrase. The biochemical studies presented here and in earlier reports support the notion that once recruited to a promoter or enhancer, the SWI/SNF complex has the potential to enhance nucleosome binding by a wide range of transcription factors. Enhanced nucleosome binding by transcription factors can occur subsequent to SWI/SNF binding and nucleosome disruption because of the persistence of the disrupted state of the nucleosome core. This observation clearly illustrates that the stimulation of transcription factor binding is caused by the disrupted state of the nucleosome core and does not require transcription factor-SWI/SNF interactions. Thus, the ATP requirement for SWI/SNF function in vitro is to mediate disruption of the nucleosome cores and is only indirectly required to stimulate transcription factor binding. The persistence of the SWI/SNF-disrupted nucleosome core conformation can provide a window of opportunity for enhanced transcription factor binding that extends beyond the actual interaction of the SWI/SNF complex. In the in vitro system used here, the disrupted state of the nucleosome cores persists for up to 4 hr before reverting to the original conformation, with its low affinity for transcription factors. The persistence of the SWI/SNF-disrupted nucleosome conformation may be a regulated event in vivo. For example, the reversibility of the disrupted conformation might be enhanced by transcriptional repressors or nucleosome-nucleosome interaction. Moreover, histone modifications thought to be involved in transcriptional activity (i.e., histone acetylation) might extend the persistence of the SWI/SNF-disrupted nucleosome conformation (Cote, 1998).

INI1 (integrase interactor 1)/hSNF5 is a component of the mammalian SWI/SNF complex and a tumor suppressor mutated in malignant rhabdoid tumors (MRT). A nuclear export signal (NES) has been identified in the highly conserved repeat 2 domain of INI1 that is unmasked upon deletion of a downstream sequence. Mutation of conserved hydrophobic residues within the NES, as well as leptomycin B treatment abrogates the nuclear export. Full-length INI1 specifically associates with hCRM1/exportin1 in vivo and in vitro. A mutant INI1 [INI1(1-319) delG950] found in MRT lacking the 66 C-terminal amino acids mislocalizes to the cytoplasm. Full-length INI1 but not the INI1(1-319 delG950) mutant causes flat cell formation and cell cycle arrest in cell lines derived from MRT. Disruption of the NES in the delG950 mutant causes nuclear localization of the protein and restored its ability to cause cell cycle arrest. These observations demonstrate that INI1 has a masked NES that mediates regulated hCRM1/exportin1-dependent nuclear export and it is proposed that mutations that cause deregulated nuclear export of the protein could lead to tumorigenesis (Craig, 2002).

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Snf5-related 1: Biological Overview | Regulation | Developmental Biology | Effects of Mutation | References

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