Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of cAMP response-element binding protein (CREB)-binding protein (CBP) to function as a co-activator for a number of transcription factors appears to be mediated by its ability to act as a histone acetyltransferase and through its interaction with a number of other proteins (general transcription factors, histone acetyltransferases, and other co-activators). Here we report that CBP also interacts with a novel ATPase termed Snf2-Related CBP Activator Protein (SRCAP). Consistent with this activity, SRCAP contains the conserved ATPase domain found within members of the Snf2 family. Transfection experiments demonstrate that SRCAP is able to activate transcription when expressed as a Gal-SRCAP chimera and that SRCAP also enhances the ability of CBP to activate transcription. The adenoviral protein E1A was found to disrupt interaction between SRCAP and CBP possibly representing a mechanism for E1A-mediated transcriptional repression.
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PMID:Identification of a novel SNF2/SWI2 protein family member, SRCAP, which interacts with CREB-binding protein. 1034 96

Chromatin structure is inextricably linked to transcription regulation and differentiation. It consists of a multicomponent system, and impairments in such complex arrays may elicit dramatic biological effects and diseases. We present an overview of human genes involved in chromatin remodeling, which consist of the histone acetyltransferase/deacetylase system and the SWI/SNF-like complexes containing DNA-dependent ATPase activity. Special attention is given to the functional and physical interactions in which these components are involved, notably as transcriptional coactivators and/or corepressors of a large variety of genes. Linking seemingly distinct pathways allows integration of individual components into complex genetic and molecular processes and assessment of the underlying molecular bases of diseases. This was performed using GENATLAS (http://www.infobiogen.fr/), a gene database which compiles the information relevant to the mapping efforts from the published literature.
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PMID:Human genes involved in chromatin remodeling in transcription initiation, and associated diseases: An overview using the GENATLAS database. 1044 37

The SWI-SNF and SAGA complexes possess ATP-dependent nucleosome remodelling activity and histone acetyltransferase (HAT) activity, respectively. Mutations that eliminate the ATPase activity of the SWI-SNF complex, or the HAT activity of SAGA, abolish proper chromatin remodelling at the PHO8 promoter in vivo. These effects are mechanistically distinct, since the absence of SWI-SNF freezes chromatin in the repressed state, while the absence of Gcn5 permits a localized perturbation of chromatin structure immediately adjacent to the upstream transactivator binding site. However, this remodelling is not propagated to the proximal promoter, and no activation is observed under all conditions. Furthermore, Pho4 is bound to the PHO8 promoter in the absence of Snf2 or Gcn5, confirming a role for SWI-SNF and SAGA in chromatin remodelling independent of activator binding. These data provide new insights into the roles of the SWI-SNF and SAGA complexes in chromatin remodelling in vivo.
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PMID:Chromatin remodelling at the PHO8 promoter requires SWI-SNF and SAGA at a step subsequent to activator binding. 1056 52

It is well known that histone acetylases are important chromatin modifiers and that they play a central role in chromatin transcription. Here, we present evidence for novel roles of histone acetylases. The TIP60 histone acetylase purifies as a multimeric protein complex. Besides histone acetylase activity on chromatin, the TIP60 complex possesses ATPase, DNA helicase, and structural DNA binding activities. Ectopic expression of mutated TIP60 lacking histone acetylase activity results in cells with defective double-strand DNA break repair. Importantly, the resulting cells lose their apoptotic competence, suggesting a defect in the cells' ability to signal the existence of DNA damage to the apoptotic machinery. These results indicate that the histone acetylase TIP60-containing complex plays a role in DNA repair and apoptosis.
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PMID:Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. 1096 8

Dosage compensation in Drosophila is mediated by a multiprotein, RNA-containing complex that associates with the X chromosome at multiple sites. We have investigated the role that the enzymatic activities of two complex components, the histone acetyltransferase activity of MOF and the ATPase activity of MLE, may have in the targeting and association of the complex with the X chromosome. Here we report that MLE and MOF activities are necessary for complexes to access the various X chromosome sites. The role that histone H4 acetylation plays in this process is supported by our observations that MOF overexpression leads to the ectopic association of the complex with autosomal sites.
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PMID:Targeting the chromatin-remodeling MSL complex of Drosophila to its sites of action on the X chromosome requires both acetyl transferase and ATPase activities. 1101 22

Mutations in Drosophila ISWI, a member of the SWI2/SNF2 family of chromatin remodeling ATPases, alter the global architecture of the male X chromosome. The transcription of genes on this chromosome is increased 2-fold relative to females due to dosage compensation, a process involving the acetylation of histone H4 at lysine 16 (H4K16). Here we show that blocking H4K16 acetylation suppresses the X chromosome defects resulting from loss of ISWI function in males. In contrast, the forced acetylation of H4K16 in ISWI mutant females causes X chromosome defects indistinguishable from those seen in ISWI mutant males. Increased expression of MOF, the histone acetyltransferase that acetylates H4K16, strongly enhances phenotypes resulting from the partial loss of ISWI function. Peptide competition assays revealed that H4K16 acetylation reduces the ability of ISWI to interact productively with its substrate. These findings suggest that H4K16 acetylation directly counteracts chromatin compaction mediated by the ISWI ATPase.
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PMID:Modulation of ISWI function by site-specific histone acetylation. 1188 43

Actin-related proteins share significant homology with conventional actins and are classified into subfamilies based on the similarity of their sequences and functions. The Arp4 subfamily of Arps is localized in the nucleus, and a mammalian isoform, ArpNbeta (also known as BAF53), is a component of the chromatin remodeling and histone acetyltransferase complexes. Another isoform identified in humans, ArpNalpha has scarcely been characterized yet. We identified mouse ArpNalpha, and showed that ArpNalpha is more similar between humans and mice than ArpNbeta. No difference was observed between ArpNalpha and beta in subcellular localization and interaction with BRM, which is an ATPase subunit of mammalian SWI/SNF chromatin remodeling complex. However, ArpNalpha was expressed exclusively in the brain and its expression was induced during neural differentiation of P19 mouse embryonic carcinoma cells. ArpNalpha is the first brain-specific component of a chromatin remodeling complex to be identified, suggesting that ArpNalpha has conserved and important roles in the differentiation of neural cells through regulation of chromatin structure.
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PMID:Brain-specific expression of the nuclear actin-related protein ArpNalpha and its involvement in mammalian SWI/SNF chromatin remodeling complex. 1243 90

Beta-catenin has a key role in Wnt signaling via effects on T-cell factor (TCF)-mediated transcription. Mutational defects in beta-catenin regulation are seen in many cancers, leading to elevated beta-catenin levels, enhanced binding of beta-catenin to TCFs, and increased expression of TCF-regulated genes. Factors cooperating with beta-catenin in transcription of TCF-regulated genes are not well defined. TIP49, an ATPase previously implicated as a cofactor for oncogenic transformation by c-Myc, has been shown to bind to beta-catenin. We found that expression of an ATPase-deficient mutant form of TIP49 (TIP49D302N) substantially inhibited beta-catenin-mediated neoplastic transformation of immortalized rat epithelial cells and anchorage-independent growth of human colon cancer cells with deregulated beta-catenin. The TIP49D302N mutant inhibited beta-catenin-mediated activation of TCF-dependent cellular genes. Similar inhibition of the expression of beta-catenin/TCF-dependent genes was seen with small interfering RNA approaches against endogenous TIP49. TIP49 was found in complexes with chromatin remodeling and histone-modifying factors and cofactors, including the TIP60 histone acetylase-associated proteins transactivation/transformation-domain associated protein (TRRAP) and BAF53. Using chromatin immunoprecipitation methods, the TIP49, TIP60, and TRRAP proteins were found to interact with sequences in the regulatory region of the gene for ITF-2, a TCF-dependent cellular gene. The ability of TIP49D302N to inhibit ITF-2 gene expression was linked to decreased acetylation of histones in the vicinity of the TCF-binding sites in the ITF-2 promoter region. We suggest that TIP49 is an important cofactor in beta-catenin/TCF gene regulation in normal and neoplastic cells, likely functioning in chromatin remodeling.
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PMID:TIP49 regulates beta-catenin-mediated neoplastic transformation and T-cell factor target gene induction via effects on chromatin remodeling. 1469 87

The NuA4 histone acetyltransferase (HAT) multisubunit complex is responsible for acetylation of histone H4 and H2A N-terminal tails in yeast. Its catalytic component, Esa1, is essential for cell cycle progression, gene-specific regulation and has been implicated in DNA repair. Almost all NuA4 subunits have clear homologues in higher eukaryotes, suggesting that the complex is conserved throughout evolution to metazoans. We demonstrate here that NuA4 complexes are indeed present in human cells. Tip60 and its splice variant Tip60b/PLIP were purified as stable HAT complexes associated with identical polypeptides, with 11 of the 12 proteins being homologs of yeast NuA4 subunits. This indicates a highly conserved subunit composition and the identified human proteins underline the role of NuA4 in the control of mammalian cell proliferation. ING3, a member of the ING family of growth regulators, links NuA4 to p53 function which we confirmed in vivo. Proteins specific to the human NuA4 complexes include ruvB-like helicases and a bromodomain-containing subunit linked to ligand-dependent transcription activation by the thyroid hormone receptor. We also demonstrate that subunits MRG15 and DMAP1 are present in distinct protein complexes harboring histone deacetylase and SWI2-related ATPase activities, respectively. Finally, analogous to yeast, a recombinant trimeric complex formed by Tip60, EPC1, and ING3 is sufficient to reconstitute robust nucleosomal HAT activity in vitro. In conclusion, the NuA4 HAT complex is highly conserved in eukaryotes, in which it plays primary roles in transcription, cellular response to DNA damage, and cell cycle control.
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PMID:Structural and functional conservation of the NuA4 histone acetyltransferase complex from yeast to humans. 1496 70

The conserved histone variant H2A.Z functions in euchromatin to antagonize the spread of heterochromatin. The mechanism by which histone H2A is replaced by H2A.Z in the nucleosome is unknown. We identified a complex containing 13 different polypeptides associated with a soluble pool of H2A.Z in Saccharomyces cerevisiae. This complex was designated SWR1-Com in reference to the Swr1p subunit, a Swi2/Snf2-paralog. Swr1p and six other subunits were found only in SWR1-Com, whereas six other subunits were also found in the NuA4 histone acetyltransferase and/or the Ino80 chromatin remodeling complex. H2A.Z and SWR1 were essential for viability of cells lacking the EAF1 component of NuA4, pointing to a close functional connection between these two complexes. Strikingly, chromatin immunoprecipitation analysis of cells lacking Swr1p, the presumed ATPase of the complex, revealed a profound defect in the deposition of H2A.Z at euchromatic regions that flank the silent mating type cassette HMR and at 12 other chromosomal sites tested. Consistent with a specialized role for Swr1p in H2A.Z deposition, the majority of the genome-wide transcriptional defects seen in swr1Delta cells were also found in htz1Delta cells. These studies revealed a novel role for a member of the ATP-dependent chromatin remodeling enzyme family in determining the region-specific histone subunit composition of chromatin in vivo and controlling the epigenetic state of chromatin. Metazoan orthologs of Swr1p (Drosophila Domino; human SRCAP and p400) may have analogous functions.
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PMID:A protein complex containing the conserved Swi2/Snf2-related ATPase Swr1p deposits histone variant H2A.Z into euchromatin. 1504 29


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