Snf5-related 1

Protein Interactions

The SNR1 and BRM proteins are present in a large (> 2 x 10(6) Da) complex, and they co-immunoprecipitate from Drosophila extracts (Dingwall, 1995).

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. Yeast two hybrid screening of a Drosophila cDNA library was performed and interaction was detected between a Trx polypeptide spanning SET and the Snr1 protein. Snr1 is a product of snr1, which is classified as a trx group gene. Parallel interaction is found 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 is detected at discrete sites on larval salivary gland polytene chromosomes, and these sites colocalize with approximately 50% 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 observed interactions suggest a mechanism by which the SWI/SNF complex is recruited to ALL-1/trx targets through physical interactions of the C-terminal domains of ALL-1 and Trx with INI1/Snr1 (Rozenblatt-Rosen, 1998).

The Drosophila osa gene, like yeast SWI1, encodes an AT-rich interaction (ARID) domain protein. Genetic and biochemical evidence is presented that Osa is a component of the Brahma complex, the Drosophila homolog of SWI/SNF. To determine whether Osa is associated with the high molecular weight Brm complex, Schneider cell nuclear extracts were fractionated through a glycerol gradient and immunoblotted with antibodies against the various proteins. Osa, Brm and Snr1 co-sediment in the bottom third of the gradient, suggesting that they are part of a large protein complex. Although Osa and Brm are present in similar fractions, Snr1 sediments in the bottom half of the gradient and could also be part of another complex that does not contain Osa or Brm. Alternatively, the anti-Snr1 antibody might be much more sensitive, detecting very low levels of the Snr1 protein. When glycerol gradient fractions are immunoprecipitated with anti-Osa antibody, Osa, Brm and Snr1 co-precipitate in the same region of the gradient in which they co-sediment. ISWI and Ash2 both show broad sedimentation patterns, appearing in the bottom half of the gradient, but neither protein is immunoprecipitated from the gradient fractions with anti-Osa antibody. Thus, in vivo, Osa is found in a large complex with Brm and Snr1, but does not bind to proteins in other chromatin remodeling complexes. The ARID domain of Osa binds DNA without sequence specificity in vitro, but it is sufficient to direct transcriptional regulatory domains to specific target genes in vivo. Endogenous Osa appears to promote the activation of some of these genes. Some Brahma-containing complexes do not contain Osa and Osa is not required to localize Brahma to chromatin. These data suggest that Osa modulates the function of the Brahma complex (Collins, 1999).

osa genetically interacts with trithorax group genes. Ectopic expression of a dominant-negative form of Brm with a mutation in the ATP binding site (UAS-brm^K804R) disrupts many developmental processes. An optomotor-blind (omb)-GAL4 driver was used to direct expression of UAS-brm^K804R in the central region of the wing disc; this results in loss of the distal wing margin, formation of ectopic campaniform sensillae and wing margin bristles, and disruptions in wing vein morphology. These phenotypes are strongly enhanced in animals heterozygous for osa. Expression of UAS-brm^K804R at the wing margin using vestigial (vg)-GAL4 results in the loss of the proximal, posterior wing margin, a phenotype that is again enhanced in osa heterozygotes. The effect of increasing osa dosage was tested by co-expressing a full-length osa transcript under the control of the same vg-GAL4 driver, and this completely rescues the dominant-negative Brm phenotype. Interestingly, ectopic expression of osa alone with vg-Gal4 induces a dominant loss of proximal wing hinge structures, and this phenotype is also rescued in animals co-expressing osa and dominant-negative brm. This suggests that the functions of Osa and Brm are closely related, because a reduction in the activity of one can compensate for an excess of the other (Collins, 1999).

Ectopic expression of Osa in eye imaginal discs using eyeless (ey)-GAL4 results in a variable reduction in eye size. Rather than the expected suppression, an enhancement of this phenotype has been observed in flies that either co-express dominant-negative Brm or are heterozygous for brm. The eye phenotype is also enhanced by mor and SNF5-related 1 (Snr1), both of which encode components of the Brm complex. However, reducing the dosage of the trithorax group genes trx, ash1 or ash2 does not enhance the Osa overexpression phenotype. As expected, a reduction in osa dosage suppresses the small eye phenotype. Clones of mor mutant cells in the eye disc exhibit a severe reduction in growth, which is partially rescued if the cells are also mutant for osa. Taken together, these data demonstrate that osa shows strong and specific genetic interactions with components of the Brm complex. However, in the wing, osa appears to act in concert with brm, whereas in the eye, osa opposes the functions of brm, snr1 and mor (Collins, 1999).

Cyclin E-Cdk2 is essential for S phase entry. To identify genes interacting with cyclin E, a genetic screen was carried out using a hypomorphic mutation of Drosophila cyclin E (DmcycE^JP), which gives rise to adults with a rough eye phenotype. Among the dominant suppressors of DmcycE^JP, brahma (brm) and moira (mor) were identified. These genes encode conserved core components of the Drosophila Brm complex that is highly related to the SWI-SNF ATP-dependent chromatin remodeling complex. Mutations in genes encoding other Brm complex components, including snr1 (BAP45), osa and deficiencies that remove BAP60 and BAP111 can also suppress the DmcycE^JP eye phenotype. Brm complex mutants suppress the DmcycE^JP phenotype by increasing S phases without affecting DmcycE protein levels. DmcycE physically interacts with Brm and Snr1 in vivo. These data suggest that the Brm complex inhibits S phase entry by acting downstream of DmcycE protein accumulation. The Brm complex also physically interacts weakly with Drosophila retinoblastoma (Rbf1), but no genetic interactions were detected, suggesting that the Brm complex and Rbf1 act largely independently to mediate G₁ arrest (Brumby, 2002).

The genetic interactions with DmcycE or E2F1/DP and Brm complex genes initially were thought to be due to effects on DmcycE transcription or E2F/DP-dependent transcription, given the role of the Brm complex in transcriptional regulation. Surprisingly, the results of this study suggest that the Brm complex functions downstream of DmcycE transcription and protein accumulation. (1) No significant effect on DmcycE protein levels in DmcycE^JP eye discs was observed when the dosage of brm or mor was halved. (2) The rough eye phenotype due to overexpression of DmcycE from the GMR driver is enhanced by halving the dosage of brm and mor, indicating that Brm and Mor act to inhibit S phase entry downstream of DmcycE transcription. (3) DmcycE forms a complex with Brm and Snr1. Taken together, these data provide strong evidence that the Brm complex does not inhibit the G₁ to S phase transition by acting to down-regulate DmcycE transcription (Brumby, 2002).

Consistent with studies in cultured mammalian cells, the Rbf1 protein was found to be present in complexes with Brm or Snr1 in larval and embryonic extracts. However, in embryos, only a small portion of total cellular Rbf1 is present in Snr1 immunoprecipitates, in contrast to a significant fraction of the cellular DmcycE, suggesting that most Brm complexes do not contain Rbf1. The observation that Drosophila Rbf1 and Brm form a complex in vivo is consistent with studies in mammalian cells showing that hBrm and/or Brg1 can bind to and cooperate with Rb in transcriptional repression, and that hBrm and Brg1 are required for Rb-induced G₁ arrest. However, in Drosophila, no clear evidence was obtained for cooperation of brm or mor with rbf1 in S phase entry. It is possible that the phenotypes being examining were not sensitive enough for S phase effects to be observed. However, the lack of a strong effect of Brm complex mutants on the rbf1 mutant S phase phenotype, when strong genetic interactions were observed with Brm complex genes and DmcycE, suggests that Rbf1 and Brm primarily function independently in negatively regulating S phase entry. Therefore, the suppression of the S phase defect of DmcycE^JP by Brm complex mutants may not involve rbf1. Independent roles for Brm and Rb are also likely in mammalian cells since Rb knockout mice have a different mutant phenotype from that of Brg1 or Brm knockouts (Brumby, 2002).

In mammalian cells, Rb can form a complex containing both Brg1 and Hdac1, which is required to repress DmcycE transcription and may also have a role at replication origins. However, reducing the dose of the Drosophila Hdac gene, rpd3, did not suppress the DmcycE^JP rough eye phenotype. It is possible that no interaction was observed for rpd3 and DmcycE, because there are a least three other Hdacs in flies that may perform overlapping functions with rpd3. However, mutations in sin3a, which encodes a Hdac-interacting protein, enhance the DmcycE^JP rough eye phenotype, suggesting that Sin3a functions in opposition to Brm in regulating DmcycE or S phase entry. Further studies using specific mutations in other Drosophila Hdacs, and Hdac-interacting proteins are required to analyze further their role in the G₁ to S phase transition (Brumby, 2002).

How does the Brm complex mediate negative regulation of the G₁ to S phase transition? The results suggest that the Brm complex is playing a role independent of DmcycE transcription and E2F/DP-dependent transcription in negatively regulating the G₁ to S phase transition. One way in which this may occur is by transcriptional regulation of other critical G₁/S phase genes. For example, there is evidence that in Drosophila, the Brm complex is important in negatively regulating Armadillo-dTCF target genes in the Wingless signaling pathway. Although as yet there have been no studies showing directly that G₁/S phase-inducing genes are targets of the Wingless signaling pathway in Drosophila, this is possible based on studies in mammalian cells. Furthermore, the Wingless pathway clearly has a role in cell proliferation in some Drosophila tissues. Whether this is the mechanism by which the Brm complex mediates negative regulation of cell cycle entry requires further investigation (Brumby, 2002).

Another way in which the Brm complex may function is by restricting or regulating access to chromosomal origins of replication. Several studies have shown that ATP-dependent chromatin remodeling is important for modulating the initiation of chromosomal DNA replication. The data are consistent with the view that the Brm complex may play a role in this process, possibly functioning to restrict entry into S phase by acting directly to remodel nucleosomes at replication origins. In this scenario, DmcycE-Cdk2 may then act to phosphorylate and inactivate the Brm complex, allowing assembly or function of the pre-replication complex and replication origin firing. Indeed, cyclin E-Cdk2 has been shown to be recruited by the Cdc6 pre-replication complex protein to replication origins at the G₁ to S phase transition (Brumby, 2002).

In summary, these results have shown that mutations in genes encoding components of the Brm chromatin remodeling complex can dominantly suppress a DmcycE hypomorphic allele by increasing the number of S phase cells without affecting cyclin E protein levels. Consistent with this view, DmcycE physically interacts with Brm and Snr1. Although a complex was also observed between the Brm complex and Rbf1, no genetic interactions have been detected between Brm complex genes and rbf1, suggesting that Rbf1 and Brm function largely independently in negatively regulating the G₁ to S phase transition. Taken together, these data suggest that the Brm complex negatively regulates entry into S phase, possibly in partial collaboration with Rbf1, and that this negative regulation can be abrogated by the action of cyclin E at the G₁ to S phase transition (Brumby, 2002).

DEVELOPMENTAL BIOLOGY

Embryonic

See the embryonic expression pattern of Snr1 at the Berkeley Drosophila Genome Project Patterns of Gene Expression Site.

The spatial and temporal patterns of expression of snr1 are similar to those of brm. The highest level of mRNA occurs in unfertilized eggs and early embryos. The level decreases until the end of embryogenesis, when little SNR1 mRNA is detected. Early in development SNR1 mRNA is found ubiquitously but later expression is confined to the ventral cord (CNS) and brain (Dingwall, 1995).

Effects of Mutation or Deletion

The snr1 gene is essential for normal development; genetically it interacts with brm and trithorax, suggesting cooperation in regulating homeotic gene transcription. Both snr1 and brm mutations, suppresses mutations in Polycomb (Dingwall, 1995).

The Drosophila Brahma (brm) complex, a counterpart of the Saccharomyces cerevisiae SWI/SNF ATP-dependent chromatin remodeling complex, is important for proper development by maintaining specific gene expression patterns. The Snr1 subunit is strongly conserved with yeast SNF5 and mammalian INI1 and is required for full activity of the brm complex. A temperature-sensitive allele of snr1 has been identified, caused by a single amino acid substitution in the conserved repeat 2 region, implicated in a variety of protein-protein interactions. Genetic analyses of snr1^E1 reveal that it functions as an antimorph and that snr1 has critical roles in tissue patterning and growth control. Temperature shifts show that snr1 is continuously required, with essential functions in embryogenesis, pupal stages, and adults. Allele-specific genetic interactions between snr1^E1 and mutations in genes encoding other members of the Brm complex suggest that snr1^E1 mutant phenotypes result from reduced Brm complex function. Consistent with this view, Snr1^E1 is stably associated with other components of the Brm complex at the restrictive temperature. Snr1 can establish direct contacts through the conserved repeat 2 region with the SET domain of the homeotic regulator Trithorax, and Snr1^E1 is partially defective for functional Trx association. Since truncating mutations of INI1 are strongly correlated with aggressive cancers, these results support the view that Snr1, and specifically the repeat 2 region, has a critical role in mediating cell growth control functions of the metazoan SWI/SNF complexes (Merenda, 2003).

SNR1 is an essential subunit of the Drosophila Brahma (Brm) ATP-dependent chromatin remodeling complex, with counterparts in yeast (SNF5) and mammals (INI1). Increased cell growth and wing patterning defects are associated with a conditional snr1 mutant, while loss of INI1 function is directly linked with aggressive cancers, suggesting important roles in development and growth control. The Brm complex is known to function during G₁ phase, where it appears to assist in restricting entry into S phase. In Drosophila, the activity of DmcycE/CDK2 is rate limiting for entry into S phase and the Brm complex can suppress a reduced growth phenotype associated with a hypomorphic DmcycE mutant. The results reveal that SNR1 helps mediate associations between the Brm complex and DmcycE/CDK2 both in vitro and in vivo. Further, disrupting snr1 function suppresses DmcycE^JP phenotypes, and increased cell growth defects associated with the conditional snr1^E1 mutant are suppressed by reducing DmcycE levels. While the snr1^E1-dependent increased cell growth does not appear to be directly associated with altered expression of G₁ or G₂ cyclins, transcription of the G₂-M regulator string/cdc25 is reduced. Thus, in addition to important functions of the Brm complex in G₁-S control, the complex also appears to be important for transcription of genes required for cell cycle progression (Zraly, 2004).

The conditional mutant snr1^E1 displays wing patterning defects and increased mitotic growth at both the permissive (18° C) and the restrictive (29° C) temperatures. The mutant phenotypes are sensitive to both temperature of incubation and snr1 gene dosage, indicating that they specifically result from reduced or compromised SNR1 function, rather than from complete disruption of Brm complex activities. In contrast to the use of null alleles that may reduce total complex number by half, snr1^E1 produces a stable protein that is assembled into Brm complexes at both temperatures, thus allowing complexes to form and bind their targets, but then are defective in some other function of the complex. This point is critical for these studies, since there are significantly different effects resulting from complete loss of functional Brm complexes or activities as contrasted with impaired functions that result from the incorporation of defective subunits. To help understand the functional roles of SNR1 within the conserved Brm ATP-dependent chromatin remodeling complex during metazoan development, advantage was taken of these dosage- and temperature-dependent snr1^E1 phenotypes, as well as the brm^K804R dominant-negative, both of which result in the incorporation of defective subunits (Zraly, 2004).

This report shows that snr1 can genetically interact with a subset of genes involved in cell cycle control. In addition, co-immunoprecipitation of DmcycE/CDK2 and the Brm complex indicate that stable complexes could form in vivo, while both GST-pulldown and yeast two-hybrid studies suggest that residues within SNR1 might help mediate or stabilize these contacts. SNR1 is strongly conserved with counterparts in yeast (SNF5) and mammals (INI1). The most conserved portions among SNR1-related proteins occur within the ~200-amino-acid C-terminal region comprising two imperfect repeats and a coiled coil. The repeat regions are important for contacts with a variety of cellular factors, including Drosophila Bicoid, the HOX gene regulators TRX and HRX/MLL, c-MYC as well as the viral-encoded proteins HIV integrase and HPV E1. In addition, yeast SNF5 is involved in direct associations with the GAL4 transcriptional activator. Contacts with conserved features of SNR1 are important for recruiting or modulating Drosophila Brm complex functions in vivo. The SNR1/DmCDK2 interaction may also be an important conserved feature, since similar contacts are observed between SNR1 C-terminal residues and mammalian CDK2 using yeast two-hybrid assays (Zraly, 2004).

Components of the mammalian Brm complexes, including the hBrm/BRG-1 and BAF155 (MOR) subunits, are phosphorylated prior to the onset of mitosis and this modification may be important for restricting or modulating complex activity. However, the cell cycle kinase involved and specific target residues within Brm complex components have not been identified. On the basis of work from cultured mammalian cells and the results reported in this study, CycE/CDK2 appears to be among the likely candidates for important regulatory kinase functions during portions of the cell cycle (Zraly, 2004).

CDK2 is capable of forming contacts with SNR1 through the Repeat 2 and coiled-coil regions. What might be the importance of the SNR1-CDK2 interaction? SNR1 and INI1 do not contain any obvious CDK2 phosphorylation sites and SNR1 does not appear to be a phosphoprotein, since assays using a variety of general protein phosphatases produce no detectable change in SNR1 electrophoretic migration on SDS-PAGE gels. This may be misleading, since other putative phosphoproteins, including Drosophila RBF, do not change electrophoretic mobility when treated with phosphatases. However, yeast SFH1p found in the SWI/SNF-related RSC complex and a close relative of SNR1/INI1/SNF5 appears to be phosphorylated during G₁ phase. Thus, while SNR1 does not appear to be the likely direct target for DmcycE/CDK2 regulation, the genetic results suggest the possibility that contacts between SNR1 and CDK2 may serve to stabilize or regulate interactions between DmcycE/CDK2 and the Brm complex or help to direct kinase activity, targeted either to other components of the Brm complex or to unknown cellular proteins (Zraly, 2004).

How might interactions between the Brm chromatin remodeling complex and DmcycE/CDK2 contribute to appropriate cell cycle regulation? A growing body of evidence strongly suggests that ATP-dependent chromatin remodeling complexes perform essential functions in controlling normal mitotic cell cycles. For example, the SWI/SNF complex is important for the expression of mitotic genes and DNA replication in yeast. In mammals, the Brm-related complexes functionally interact with histone deacetylases and pRB to block entry into S phase. As a consequence of losing or misregulating chromatin remodeling activities, normal cell cycle control is disrupted. Specifically, loss of INI1 is associated with aggressive cancers, leads to the rapid development of tumors in knockout mice, and results in G₁-specific defects. Further, overexpression of Cyclin E can abrogate cell cycle arrest caused by the introduction of BRG1 into SW13 adenocarcinoma cells (Zraly, 2004).

The requirements for ATP-dependent chromatin remodeling activities during the cell cycle are likely to be quite complex, perhaps involving known functions in controlling gene transcription (activation and repression) and/or regulating aspects of chromosome replication. In cultured mammalian cells, INI1 was shown to repress cyclinD1 transcription in G₁ phase through collaboration with HDAC1. Unlike mammalian cyclinD, Drosophila DmcycD is not required for entry into S phase, but has been proposed to function during G₁ to regulate cell growth. While snr1^E1 mutant phenotypes are sensitive to Cyclin D levels, the expression of DmcycD is unaffected in the mutant, consistent with the view that the snr1^E1 growth defects are likely due to misregulation of genes downstream of DmcycE, possibly involving targets of E2F regulation (Zraly, 2004).

In addition to demonstrating Brm complex regulation of gene expression during the S and G₂ phases, these results also suggest RNA PolII-independent roles in restricting S-phase entry. For example, SNR1 is excluded from mitotic chromatin during the early embryonic nuclear divisions in the absence of zygotic transcription or G₁-G₂ phases. During these early divisions, type II DmcycE is a potent inducer of S phase and this form exhibits strong in vivo associations with SNR1. One scenario is that the Brm complex is recruited to specific chromosomal sites by sequence-specific repressors where the complex might act to stabilize binding of the repressor and/or remodel nucleosomes in an ATP-dependent manner, thereby establishing a repressive environment to restrict replication initiation. The cellular proteins involved in potentially recruiting the Brm complex to specific loci involved in replication initiation are not presently known, but may include transcription factors, such as RBF/E2F or ORC. Recruitment of CycE/CDK2 to replication origins and interaction with SNR1 might then allow for inactivation of Brm activity and release of the complex from chromatin through phosphorylation of specific subunits. The SNR1^E1 mutant protein likely compromises one or more of these interactions, reducing the effective recruitment of the Brm complex to targets that are normally repressed by Brm complex activities. This could possibly lead to compromised S-phase restriction, partly relieving the requirement for DmcycE/CDK2 activity to allow progression into S phase (Zraly, 2004).

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date revised: 15 April 2007

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