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

Identity

Other names	BRG1
	BRG-1
	BAF190
	FLJ39786
	hSNF2b
	NM_003072
	SNF2-beta
	SNF2B
	SNF2L4
	SNF2LB
	SWI2
HGNC	SMARCA4
Location	19p13.2
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	SMARCA4   11100
Entrez_Gene	SMARCA4  6597  SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4
	Cards
Atlas	SMARCA4ID42333ch19p13
GeneCards	SMARCA4
Ensembl	SMARCA4 [Search_View]   ENSG00000127616 [Gene_View]
Genatlas	SMARCA4
GeneLynx	SMARCA4
eGenome	SMARCA4
euGene	6597
	Genomic and cartography
GoldenPath	SMARCA4  -  19p13.2   chr19:10932598-11033958 +  19p13.2   [Description]    (hg18-Mar_2006)
Ensembl	SMARCA4 - 19p13.2 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	SMARCA4
	Gene and transcription
Genbank	AB209313 [ ENTREZ ]
Genbank	AI695800 [ ENTREZ ]
Genbank	AK026573 [ ENTREZ ]
Genbank	AK055168 [ ENTREZ ]
Genbank	AK097105 [ ENTREZ ]
RefSeq	NM_001128844 [ SRS ]    NM_001128844 [ ENTREZ ]
RefSeq	NM_001128845 [ SRS ]    NM_001128845 [ ENTREZ ]
RefSeq	NM_001128846 [ SRS ]    NM_001128846 [ ENTREZ ]
RefSeq	NM_001128847 [ SRS ]    NM_001128847 [ ENTREZ ]
RefSeq	NM_001128848 [ SRS ]    NM_001128848 [ ENTREZ ]
RefSeq	NM_001128849 [ SRS ]    NM_001128849 [ ENTREZ ]
RefSeq	NM_003072 [ SRS ]    NM_003072 [ ENTREZ ]
RefSeq	AC_000062 [ SRS ]    AC_000062 [ ENTREZ ]
RefSeq	AC_000151 [ SRS ]    AC_000151 [ ENTREZ ]
RefSeq	NC_000019 [ SRS ]    NC_000019 [ ENTREZ ]
RefSeq	NT_011295 [ SRS ]    NT_011295 [ ENTREZ ]
RefSeq	NW_001838483 [ SRS ]    NW_001838483 [ ENTREZ ]
RefSeq	NW_927195 [ SRS ]    NW_927195 [ ENTREZ ]
AceView	SMARCA4 AceView - NCBI
Unigene	Hs.327527 [ SRS ]    Hs.327527 [ NCBI ]     HS327527 [ spliceNest ]
Fast-db	6479 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P51532 [ SRS]    P51532 [ EXPASY ]     P51532 [ INTERPRO ]     P51532 [ UNIPROT ]
Prosite	PS00633 BROMODOMAIN_1 [ SRS ]    PS00633 BROMODOMAIN_1 [ Expasy ]
Prosite	PS50014 BROMODOMAIN_2 [ SRS ]    PS50014 BROMODOMAIN_2 [ Expasy ]
Prosite	PS51192 HELICASE_ATP_BIND_1 [ SRS ]    PS51192 HELICASE_ATP_BIND_1 [ Expasy ]
Prosite	PS51194 HELICASE_CTER [ SRS ]    PS51194 HELICASE_CTER [ Expasy ]
Prosite	PS51204 HSA [ SRS ]    PS51204 HSA [ Expasy ]
Interpro	IPR006576 BRK [ SRS ]    IPR006576 BRK [ EBI ]
Interpro	IPR001487 Bromodomain [ SRS ]    IPR001487 Bromodomain [ EBI ]
Interpro	IPR014001 DEAD-like_N [ SRS ]    IPR014001 DEAD-like_N [ EBI ]
Interpro	IPR001650 DNA/RNA_helicase_C [ SRS ]    IPR001650 DNA/RNA_helicase_C [ EBI ]
Interpro	IPR013999 HAS_subgroup [ SRS ]    IPR013999 HAS_subgroup [ EBI ]
Interpro	IPR014012 Helicase/SANT-assoc_DNA_bd [ SRS ]    IPR014012 Helicase/SANT-assoc_DNA_bd [ EBI ]
Interpro	IPR014021 Helicase_SF1/SF2_ATP-bd [ SRS ]    IPR014021 Helicase_SF1/SF2_ATP-bd [ EBI ]
Interpro	IPR006562 HSA [ SRS ]    IPR006562 HSA [ EBI ]
Interpro	IPR014978 QLQ [ SRS ]    IPR014978 QLQ [ EBI ]
Interpro	IPR000330 SNF2_N [ SRS ]    IPR000330 SNF2_N [ EBI ]
CluSTr	P51532
Pfam	PF00439 Bromodomain [ SRS ]    PF00439 Bromodomain [ Sanger ]    pfam00439 [ NCBI-CDD ]
Pfam	PF00271 Helicase_C [ SRS ]    PF00271 Helicase_C [ Sanger ]    pfam00271 [ NCBI-CDD ]
Pfam	PF07529 HSA [ SRS ]    PF07529 HSA [ Sanger ]    pfam07529 [ NCBI-CDD ]
Pfam	PF08880 QLQ [ SRS ]    PF08880 QLQ [ Sanger ]    pfam08880 [ NCBI-CDD ]
Pfam	PF00176 SNF2_N [ SRS ]    PF00176 SNF2_N [ Sanger ]    pfam00176 [ NCBI-CDD ]
Pfam	PF07533 TCH [ SRS ]    PF07533 TCH [ Sanger ]    pfam07533 [ NCBI-CDD ]
Smart	SM00592 BRK [EMBL]
Smart	SM00297 BROMO [EMBL]
Smart	SM00487 DEXDc [EMBL]
Smart	SM00490 HELICc [EMBL]
Smart	SM00573 HSA [EMBL]
Blocks	P51532
PDB	2GRC [ SRS ]    2GRC [ PdbSum ],   2GRC [ IMB ]   2GRC [ RSDB ]
PDB	2H60 [ SRS ]    2H60 [ PdbSum ],   2H60 [ IMB ]   2H60 [ RSDB ]
HPRD	04459
	Protein Interaction databases
DIP	P51532
IntAct	P51532
	Polymorphism : SNP, mutations, diseases
OMIM	603254    [ map ]
GENECLINICS	603254
SNP	SMARCA4 [dbSNP-NCBI]
SNP	NM_001128844 [SNP-NCI]
SNP	NM_001128845 [SNP-NCI]
SNP	NM_001128846 [SNP-NCI]
SNP	NM_001128847 [SNP-NCI]
SNP	NM_001128848 [SNP-NCI]
SNP	NM_001128849 [SNP-NCI]
SNP	NM_003072 [SNP-NCI]
SNP	SMARCA4 [GeneSNPs - Utah]  SMARCA4] [HGBASE - SRS]
HAPMAP	SMARCA4 [HAPMAP]
COSMIC	SMARCA4 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	SMARCA4
	General knowledge
Family Browser	SMARCA4 [UCSC Family Browser]
SOURCE	NM_001128844
SOURCE	NM_001128845
SOURCE	NM_001128846
SOURCE	NM_001128847
SOURCE	NM_001128848
SOURCE	NM_001128849
SOURCE	NM_003072
SMD	Hs.327527
SAGE	Hs.327527
Enzyme	3.6.1.- [ Enzyme-Expasy ]   3.6.1.- [ Enzyme-SRS ]   3.6.1.- [ IntEnz-EBI ]   3.6.1.- [ BRENDA ]   3.6.1.- [ KEGG ]   3.6.1.- [ WIT ]
GO	negative regulation of transcription from RNA polymerase II promoter [Amigo]  negative regulation of transcription from RNA polymerase II promoter
GO	nucleotide binding [Amigo]  nucleotide binding
GO	heterochromatin [Amigo]  heterochromatin
GO	blastocyst growth [Amigo]  blastocyst growth
GO	blastocyst hatching [Amigo]  blastocyst hatching
GO	DNA binding [Amigo]  DNA binding
GO	chromatin binding [Amigo]  chromatin binding
GO	transcription factor activity [Amigo]  transcription factor activity
GO	transcription coactivator activity [Amigo]  transcription coactivator activity
GO	helicase activity [Amigo]  helicase activity
GO	helicase activity [Amigo]  helicase activity
GO	ATP binding [Amigo]  ATP binding
GO	nucleus [Amigo]  nucleus
GO	nucleoplasm [Amigo]  nucleoplasm
GO	methylation-dependent chromatin silencing [Amigo]  methylation-dependent chromatin silencing
GO	transcription [Amigo]  transcription
GO	glial cell fate determination [Amigo]  glial cell fate determination
GO	transcription factor binding [Amigo]  transcription factor binding
GO	hydrolase activity [Amigo]  hydrolase activity
GO	forebrain development [Amigo]  forebrain development
GO	hindbrain development [Amigo]  hindbrain development
GO	identical protein binding [Amigo]  identical protein binding
GO	protein N-terminus binding [Amigo]  protein N-terminus binding
BIOCARTA	Chromatin Remodeling by hSWI/SNF ATP-dependent Complexes    [Genes]
BIOCARTA	Control of Gene Expression by Vitamin D Receptor    [Genes]
PubGene	SMARCA4
TreeFam	SMARCA4
CTD	6597 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	SMARCA4 Related clones (RZPD - Berlin)
	PubMed
PubMed	124 Pubmed reference(s) in LocusLink

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 articles	automatic search in PubMed
Last year publications	automatic search in PubMed

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Contributor(s)

Written	04-2008	Pedro 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

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:17:34 2008