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SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4)

Identity

Other namesBRG1
BRG-1
BAF190
FLJ39786
hSNF2b
NM_003072
SNF2-beta
SNF2B
SNF2L4
SNF2LB
SWI2
HGNC (Hugo) SMARCA4
LocusID (NCBI) 6597
Location 19p13.2
Location_base_pair Starts at 11071598 and ends at 11172958 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order telomere­DNM2-IL1RL1LG-MGC3262-SMARCA4-LDLR-AK075287-centromere.

DNA/RNA

 
  Relative size of the 33 coding exons of SMARCA4. The entire exon 1 is UTR (untranslated region). Exon numeration corresponds to the prevalent transcript (matching the EST EU430759).
Description The SMARCA4 is also known as BRG1 (hSWI/SNF brahma-related gene). It spans a total genomic size of 101347 bp and it is composed of 33 coding exons of varying lengths and 1 non-coding exon (exon 1).
Transcription The human SMARCA4 transcript has approximately 5500 bp and contains an open reading frame of 4845 bp, predicting a protein of 1614 amino acid residues. There are different transcripts arising from two alternative splicing sites within intron 28 and exon 30, which predict the translation of four different BRG1 protein isoforms. In addition, between exon 26 and 27 and exon 29 and 30 there are two additional exons that may constitute tissue specific transcripts.

Protein

 
  SMARCA4 conserved domains. Proline rich region, containing more than 25% of proline residues in the aminoacid sequence. HSA and BRK domains, containing motifs that may predict binding to DNA. ATPase/helicase domain, contains motifs present in the DEAD helicases superfamily, a diverse family of proteins involved in ATP-dependent RNA or DNA unwinding. Bromodomain, 110 aminoacid domain, found in many chromatin associated proteins. Bromodomains can interact specifically with acetylated lysine.
Description SMARCA4 has a molecular mass of 181349 Da. SMARCA4 is the catalytic subunit of the chromatin-remodelling complex SWI-SNF and influences transcriptional regulation by disrupting histone-DNA contacts in an ATP-dependent manner. In addition to an ATPase, the SWI/SNF complex is composed of a variety of accessory proteins, termed BAFs (BRG-1-associated factors).
Expression Widely expressed.
Localisation SMARCA4 localizes in the nucleus.
Function The SMARCA4 harbours the ATPase activity required for the chromatin remodelling activity of the SWI/SNF complex. This complex uses the energy of ATP hydrolysis to modify the interactions among histones leading to modifications of the chromatin structure and to the regulation of gene expression. The SWI/SNF complex plays a role in differentiation, development and cell cycle control. SMARCA4 binds to or it is related to important tumor suppressor proteins, including BRCA2, LKB1, RB and FANCA. Moreover, the SWI/SNF complex has been shown to modulate the transcriptional activity of steroid receptors (e.g. glucocorticoids receptors, retinoic acid receptors, androgen and estrogen receptors), CMYC and RB. SMARCA4 acts as a tumor suppressor because:
  • i) it induces cell-growth arrest after ectopic expression in deficient tumor cells;
  • ii) SMARCA4-heterozygous mice have an increased predisposition to tumor development and
  • iii) it is biallelically inactivated by homozygous deletions or combinations of deletions and mutations in several types of tumors, specially in lung cancer.
  • Homology The mammalian SWI/SNF complex contains either SMARCA4 or SMARCA2 as its central ATPase subunit. Both ATPases share 80% homology in their aminoacid sequence. However, differences in expression patterns and in the phenotypes of Brm and Brg1 knockout mice suggest specific biological roles between both ATPases.
    SMARCA2 and SMARCA4 are orthologous to the snf2/swi2 gene from S. cerevisiae and to the "brahma" (brm) gene from Drosophila. These encode proteins that are highly conserved along evolution, especially in the ATPase/helicase domain. Actually, SMARCA2 is 56% identical and 72% homologous to the Drosophila brm.

    Implicated in

    Entity Various cancers
    Note SMARCA4 somatic mutations have been identified in some cancer cell lines including those from the lung, prostate, breast, pancreas and colon. While somatic mutations have been detected in a small subset of lung primary tumors, about one third of the lung cancer cell lines of the non-small cell lung cancer type harbour inactivating SMARCA4 somatic mutations. All mutations are homozygous and most of them predict truncated proteins. The type of mutations commonly observed include nonsense, indels and large deletions. Although less frequently, missense mutations have also been reported. Four of the aminoacid substitutions found in human lung and colorectal cancer, the p.W764R, p.G1160R, p.L1163P and p.S1176C represent changes in highly conserved residues within the ATPase/helicase domain. In vitro generated mutations of some highly conserved aminoacid within this motif lead to a seriously diminished catalytic activity of SMARCA4.
    SMARCA4 germ-line mutations have not been reported so far.
    Prognosis The lost of either SMARCA4 or SMARCA2, detected by immunostaining, predicts decreased survival in some cancer patients.
      

    To be noted

    SMARCA4 is somatically mutated in a significant proportion of tumors, in particular lung cancer. Thus, SMARCA4 is a bona fide tumor suppressor gene and is clearly implicated in cancer development.
    SMARCB1, encoding another subunit of the SWI/SNF complex, is subject to bi-allelic mutations (germinal and somatic) in rhabdoid tumours, a very aggressive form of paediatric cancers.

    External links

    Nomenclature
    HGNC (Hugo)SMARCA4   11100
    Cards
    AtlasSMARCA4ID42333ch19p13
    Entrez_Gene (NCBI)SMARCA4  6597  SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4
    GeneCards (Weizmann)SMARCA4
    Ensembl (Hinxton)ENSG00000127616 [Gene_View]  chr19:11071598-11172958 [Contig_View]  SMARCA4 [Vega]
    AceView (NCBI)SMARCA4
    Genatlas (Paris)SMARCA4
    WikiGenes6597
    SOURCE (Princeton)NM_001128844 NM_001128845 NM_001128846 NM_001128847 NM_001128848 NM_001128849 NM_003072
    Genomic and cartography
    GoldenPath (UCSC)SMARCA4  -  19p13.2   chr19:11071598-11172958 +  19p13.3   [Description]    (hg19-Feb_2009)
    EnsemblSMARCA4 - 19p13.3 [CytoView]
    Mapping of homologs : NCBISMARCA4 [Mapview]
    OMIM603254   613325   614609   
    Gene and transcription
    Genbank (Entrez)AB209313 AI695800 AK026573 AK055168 AK097105
    RefSeq transcript (Entrez)NM_001128844 NM_001128845 NM_001128846 NM_001128847 NM_001128848 NM_001128849 NM_003072
    RefSeq genomic (Entrez)AC_000151 NC_000019 NC_018930 NG_011556 NT_011295 NW_001838483 NW_004929414
    Consensus coding sequences : CCDS (NCBI)SMARCA4
    Cluster EST : UnigeneHs.327527 [ NCBI ]
    CGAP (NCI)Hs.327527
    Alternative Splicing : Fast-db (Paris)GSHG0014581
    Alternative Splicing GalleryENSG00000127616
    Gene ExpressionSMARCA4 [ NCBI-GEO ]     SMARCA4 [ SEEK ]   SMARCA4 [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP51532 (Uniprot)
    NextProtP51532  [Medical]
    With graphics : InterProP51532
    Splice isoforms : SwissVarP51532 (Swissvar)
    Catalytic activity : Enzyme3.6.4.- [ Enzyme-Expasy ]   3.6.4.-3.6.4.- [ IntEnz-EBI ]   3.6.4.- [ BRENDA ]   3.6.4.- [ KEGG ]   
    Domaine pattern : Prosite (Expaxy)BROMODOMAIN_1 (PS00633)    BROMODOMAIN_2 (PS50014)    HELICASE_ATP_BIND_1 (PS51192)    HELICASE_CTER (PS51194)    HSA (PS51204)    QLQ (PS51666)   
    Domains : Interpro (EBI)BRK_domain    Bromodomain    Bromodomain_CS    Gln-Leu-Gln_QLQ    HAS_subgr    Helicase/SANT-assoc_DNA-bd    Helicase_ATP-bd    Helicase_C    P-loop_NTPase    SNF2_N   
    Related proteins : CluSTrP51532
    Domain families : Pfam (Sanger)BRK (PF07533)    Bromodomain (PF00439)    Helicase_C (PF00271)    HSA (PF07529)    QLQ (PF08880)    SNF2_N (PF00176)   
    Domain families : Pfam (NCBI)pfam07533    pfam00439    pfam00271    pfam07529    pfam08880    pfam00176   
    Domain families : Smart (EMBL)BRK (SM00592)  BROMO (SM00297)  DEXDc (SM00487)  HELICc (SM00490)  HSA (SM00573)  QLQ (SM00951)  
    DMDM Disease mutations6597
    Blocks (Seattle)P51532
    PDB (SRS)2GRC    2H60    3UVD   
    PDB (PDBSum)2GRC    2H60    3UVD   
    PDB (IMB)2GRC    2H60    3UVD   
    PDB (RSDB)2GRC    2H60    3UVD   
    Human Protein AtlasENSG00000127616
    Peptide AtlasP51532
    HPRD04459
    IPIIPI00293426   IPI00923468   IPI00900269   IPI00900338   IPI00900285   IPI01016040   IPI00900328   IPI01015598   
    Protein Interaction databases
    DIP (DOE-UCLA)P51532
    IntAct (EBI)P51532
    FunCoupENSG00000127616
    BioGRIDSMARCA4
    InParanoidP51532
    Interologous Interaction database P51532
    IntegromeDBSMARCA4
    STRING (EMBL)SMARCA4
    Ontologies - Pathways
    Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  nuclear chromatin  heterochromatin  cell morphogenesis  RNA polymerase II regulatory region sequence-specific DNA binding  RNA polymerase II transcription coactivator activity  vasculogenesis  blastocyst growth  blastocyst hatching  liver development  p53 binding  neural retina development  chromatin binding  transcription coactivator activity  transcription coactivator activity  transcription corepressor activity  helicase activity  protein binding  ATP binding  nucleus  nuclear euchromatin  perichromatin fibrils  nucleosome disassembly  chromatin remodeling  chromatin remodeling  methylation-dependent chromatin silencing  regulation of transcription from RNA polymerase II promoter  negative regulation of transcription from RNA polymerase II promoter during mitosis  glial cell fate determination  DNA-dependent ATPase activity  DNA methylation on cytosine within a CG sequence  SWI/SNF complex  stem cell maintenance  extracellular matrix organization  keratinocyte differentiation  negative regulation of cell growth  forebrain development  hindbrain development  Tat protein binding  embryonic hindlimb morphogenesis  aortic smooth muscle cell differentiation  positive regulation of DNA binding  positive regulation by host of viral transcription  histone H3 acetylation  negative regulation of transcription, DNA-dependent  negative regulation of transcription, DNA-dependent  positive regulation of transcription, DNA-dependent  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  protein N-terminus binding  embryonic organ morphogenesis  epidermis morphogenesis  androgen receptor binding  positive regulation of sequence-specific DNA binding transcription factor activity  definitive erythrocyte differentiation  heart trabecula formation  negative regulation of androgen receptor signaling pathway  histone acetyl-lysine binding  npBAF complex  npBAF complex  nBAF complex  WINAC complex  negative regulation of G1/S transition of mitotic cell cycle  
    Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  nuclear chromatin  heterochromatin  cell morphogenesis  RNA polymerase II regulatory region sequence-specific DNA binding  RNA polymerase II transcription coactivator activity  vasculogenesis  blastocyst growth  blastocyst hatching  liver development  p53 binding  neural retina development  chromatin binding  transcription coactivator activity  transcription coactivator activity  transcription corepressor activity  helicase activity  protein binding  ATP binding  nucleus  nuclear euchromatin  perichromatin fibrils  nucleosome disassembly  chromatin remodeling  chromatin remodeling  methylation-dependent chromatin silencing  regulation of transcription from RNA polymerase II promoter  negative regulation of transcription from RNA polymerase II promoter during mitosis  glial cell fate determination  DNA-dependent ATPase activity  DNA methylation on cytosine within a CG sequence  SWI/SNF complex  stem cell maintenance  extracellular matrix organization  keratinocyte differentiation  negative regulation of cell growth  forebrain development  hindbrain development  Tat protein binding  embryonic hindlimb morphogenesis  aortic smooth muscle cell differentiation  positive regulation of DNA binding  positive regulation by host of viral transcription  histone H3 acetylation  negative regulation of transcription, DNA-dependent  negative regulation of transcription, DNA-dependent  positive regulation of transcription, DNA-dependent  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  protein N-terminus binding  embryonic organ morphogenesis  epidermis morphogenesis  androgen receptor binding  positive regulation of sequence-specific DNA binding transcription factor activity  definitive erythrocyte differentiation  heart trabecula formation  negative regulation of androgen receptor signaling pathway  histone acetyl-lysine binding  npBAF complex  npBAF complex  nBAF complex  WINAC complex  negative regulation of G1/S transition of mitotic cell cycle  
    Pathways : BIOCARTAControl of Gene Expression by Vitamin D Receptor [Genes]    Chromatin Remodeling by hSWI/SNF ATP-dependent Complexes [Genes]   
    REACTOMESMARCA4
    Protein Interaction DatabaseSMARCA4
    Wikipedia pathwaysSMARCA4
    Gene fusion - rearrangments
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)SMARCA4
    SNP (GeneSNP Utah)SMARCA4
    SNP : HGBaseSMARCA4
    Genetic variants : HAPMAPSMARCA4
    1000_GenomesSMARCA4 
    ICGC programENSG00000127616 
    Cancer Gene: CensusSMARCA4 
    Somatic Mutations in Cancer : COSMICSMARCA4 
    CONAN: Copy Number AnalysisSMARCA4 
    Mutations and Diseases : HGMDSMARCA4
    OMIM603254    613325    614609   
    GENETestsSMARCA4
    Disease Genetic AssociationSMARCA4
    Huge Navigator SMARCA4 [HugePedia]  SMARCA4 [HugeCancerGEM]
    Genomic VariantsSMARCA4  SMARCA4 [DGVbeta]
    Exome VariantSMARCA4
    dbVarSMARCA4
    ClinVarSMARCA4
    snp3D : Map Gene to Disease6597
    General knowledge
    Homologs : HomoloGeneSMARCA4
    Homology/Alignments : Family Browser (UCSC)SMARCA4
    Phylogenetic Trees/Animal Genes : TreeFamSMARCA4
    Chemical/Protein Interactions : CTD6597
    Chemical/Pharm GKB GenePA35950
    Drug Sensitivity SMARCA4
    Clinical trialSMARCA4
    Cancer Resource (Charite)ENSG00000127616
    Other databases
    Probes
    Litterature
    PubMed293 Pubmed reference(s) in Entrez
    CoreMineSMARCA4
    iHOPSMARCA4

    Bibliography

    BRG1 contains a conserved domain of the SWI2/SNF2 family necessary for normal mitotic growth and transcription.
    Khavari PA, Peterson CL, Tamkun JW, Mendel DB, Crabtree GR.
    Nature. 1993 Nov 11;366(6451):170-4.
    PMID 8232556
     
    Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer.
    Versteege I, Sevenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R, Aurias A, Delattre O.
    Nature. 1998 Jul 9;394(6689):203-6.
    PMID 9671307
     
    Alteration of hSNF5/INI1/BAF47 detected in rhabdoid cell lines and primary rhabdomyosarcomas but not Wilms' tumors.
    DeCristofaro MF, Betz BL, Wang W, Weissman BE.
    Oncogene. 1999 Dec 9; 18(52): 7559-65.
    PMID 10602515
     
    ATP-dependent chromatin remodelling: SWI/SNF and Co. are on the job.
    Muchardt C, Yaniv M.
    J Mol Biol. 1999 Oct 22;293(2):187-98.
    PMID 10529347
     
    A Brg1 null mutation in the mouse reveals functional differences among mammalian SWI/SNF complexes.
    Bultman S, Gebuhr T, Yee D, La Mantia C, Nicholson J, Gilliam A, Randazzo F, Metzger D, Chambon P, Crabtree G, Magnuson T.
    Mol Cell. 2000 Dec;6(6):1287-95.
    PMID 11163203
     
    BRG-1 is required for RB-mediated cell cycle arrest.
    Strobeck MW, Knudsen KE, Fribourg AF, DeCristofaro MF, Weissman BE, Imbalzano AN, Knudsen ES.
    Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7748-53.
    PMID 10884406
     
    BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines.
    Wong AK, Shanahan F, Chen Y, Lian L, Ha P, Hendricks K, Ghaffari S, Iliev D, Penn B, Woodland AM, Smith R, Salada G, Carillo A, Laity K, Gupte J, Swedlund B, Tavtigian SV, Teng DH, Lees E.
    Cancer Res. 2000 Nov 1;60(21):6171-7.
    PMID 11085541
     
    Characterization of SWI/SNF protein expression in human breast cancer cell lines and other malignancies.
    Decristofaro MF, Betz BL, Rorie CJ, Reisman DN, Wang W, Weissman BE.
    J Cell Physiol. 2001 Jan;186(1):136-45.
    PMID 11147808
     
    When the SWI/SNF complex remodels...the cell cycle.
    Muchardt C, Yaniv M.
    Oncogene. 2001 May 28;20(24):3067-75.
    PMID 11420722
     
    Chromatin remodeling factors and BRM/BRG1 expression as prognostic indicators in non-small cell lung cancer.
    Fukuoka J, Fujii T, Shih JH, Dracheva T, Meerzaman D, Player A, Hong K, Settnek S, Gupta A, Buetow K, Hewitt S, Travis WD, Jen J.
    Clin Cancer Res. 2004 Jul 1;10(13):4314-24.
    PMID 15240517
     
    Genetic and epigenetic screening for gene alterations of the chromatin-remodeling factor, SMARCA4/BRG1, in lung tumors.
    Medina PP, Carretero J, Fraga MF, Esteller M, Sidransky D, Sanchez-Cespedes M.
    Genes Chromosomes Cancer. 2004 Oct;41(2):170-7.
    PMID 15287030
     
    The SWI/SNF complex--chromatin and cancer.
    Roberts CW, Orkin SH.
    Nat Rev Cancer. 2004 Feb;4(2):133-42.
    PMID 14964309
     
    A Brg1 mutation that uncouples ATPase activity from chromatin remodeling reveals an essential role for SWI/SNF-related complexes in beta-globin expression and erythroid development.
    Bultman SJ, Gebuhr TC, Magnuson T.
    Genes Dev. 2005 Dec 1;19(23):2849-61.
    PMID 16287714
     
    Transcriptional targets of the chromatin-remodelling factor SMARCA4/BRG1 in lung cancer cells.
    Medina PP, Carretero J, Ballestar E, Angulo B, Lopez-Rios F, Esteller M, Sanchez-Cespedes M.
    Hum Mol Genet. 2005 Apr 1;14(7):973-82.
    PMID 15731117
     
    A conserved Swi2/Snf2 ATPase motif couples ATP hydrolysis to chromatin remodeling.
    Smith CL, Peterson CL.
    Mol Cell Biol. 2005 Jul;25(14):5880-92.
    PMID 15988005
     
    Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines.
    Medina PP, Romero OA, Kohno T, Montuenga LM, Pio R, Yokota J, Sanchez-Cespedes M.
    Hum Mutat. 2008 May;29(5):617-22.
    PMID 18386774
     
    REVIEW articlesautomatic search in PubMed
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    Contributor(s)

    Written04-2008Pedro P Medina, Montse Sanchez-Cespedes
    Department of Molecular, Cellular and Developmental Biology, Yale University, 266 Whitney Ave, KBT 938, 06520. New Haven, CT, USA (PPM); Molecular pathology program, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro, 3, 28029 Madrid, Spain (MSC)

    Citation

    This paper should be referenced as such :
    Medina PP, Sanchez-Cespedes M . SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4). Atlas Genet Cytogenet Oncol Haematol. April 2008 .
    URL : http://AtlasGeneticsOncology.org/Genes/SMARCA4ID42333ch19p13.html

    The various updated versions of this paper are referenced and archived by INIST as such :
    http://documents.irevues.inist.fr/bitstream/2042/44430/1/04-2008-SMARCA4ID42333ch19p13.pdf   [ Bibliographic record ]

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    indexed on : Fri Apr 18 17:23:26 CEST 2014

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