SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4)
2008-04-01 Pedro P Medina , Montse Sanchez-Cespedes, PhD AffiliationIdentity
HGNC
LOCATION
19p13.2
LOCUSID
ALIAS
BAF190,BAF190A,BRG1,CSS4,MRD16,RTPS2,SNF2,SNF2-beta,SNF2L4,SNF2LB,SWI2,hSNF2b
FUSION GENES
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.
Proteins
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.
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 name
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.
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 11163203 | 2000 | A Brg1 null mutation in the mouse reveals functional differences among mammalian SWI/SNF complexes. | Bultman S et al |
| 16287714 | 2005 | 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 et al |
| 10602515 | 1999 | Alteration of hSNF5/INI1/BAF47 detected in rhabdoid cell lines and primary rhabdomyosarcomas but not Wilms' tumors. | DeCristofaro MF et al |
| 11147808 | 2001 | Characterization of SWI/SNF protein expression in human breast cancer cell lines and other malignancies. | Decristofaro MF et al |
| 15240517 | 2004 | Chromatin remodeling factors and BRM/BRG1 expression as prognostic indicators in non-small cell lung cancer. | Fukuoka J et al |
| 8232556 | 1993 | BRG1 contains a conserved domain of the SWI2/SNF2 family necessary for normal mitotic growth and transcription. | Khavari PA et al |
| 15731117 | 2005 | Transcriptional targets of the chromatin-remodelling factor SMARCA4/BRG1 in lung cancer cells. | Medina PP et al |
| 18386774 | 2008 | Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines. | Medina PP et al |
| 11420722 | 2001 | When the SWI/SNF complex remodels...the cell cycle. | Muchardt C et al |
| 14964309 | 2004 | The SWI/SNF complex--chromatin and cancer. | Roberts CW et al |
| 15988005 | 2005 | A conserved Swi2/Snf2 ATPase motif couples ATP hydrolysis to chromatin remodeling. | Smith CL et al |
| 10884406 | 2000 | BRG-1 is required for RB-mediated cell cycle arrest. | Strobeck MW et al |
| 9671307 | 1998 | Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. | Versteege I et al |
| 11085541 | 2000 | BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines. | Wong AK et al |
Other Information
Locus ID:
NCBI: 6597
MIM: 603254
HGNC: 11100
Ensembl: ENSG00000127616
Variants:
dbSNP: 6597
ClinVar: 6597
TCGA: ENSG00000127616
COSMIC: SMARCA4
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38117955 | 2024 | Thoracic SMARCA4-deficient undifferentiated tumor: current knowledge and future perspectives. | 0 |
| 38180245 | 2024 | Molecular and Pathologic Characterization of YAP1-Expressing Small Cell Lung Cancer Cell Lines Leads to Reclassification as SMARCA4-Deficient Malignancies. | 2 |
| 38252663 | 2024 | Brg1/PRMT5 nuclear complex epigenetically regulates FOXO1 in IPF mesenchymal progenitor cells. | 0 |
| 38306886 | 2024 | Thoracic SMARCA4-deficient undifferentiated tumor: A clinicopathological and prognostic analysis of 35 cases and immunotherapy efficacy. | 1 |
| 38311259 | 2024 | BRG1 accelerates mesothelial cell senescence and peritoneal fibrosis by inhibiting mitophagy through repression of OXR1. | 0 |
| 38348687 | 2024 | BRG1 mediates epigenetic regulation of TNFα-induced CCL2 expression in oral tongue squamous cell carcinoma cells. | 0 |
| 38413251 | 2024 | SMARCA4 deficiency and mutations are frequent in large cell lung carcinoma and are prognostically significant. | 0 |
| 38427725 | 2024 | BRG1 establishes the neuroectodermal chromatin landscape to restrict dorsal cell fates. | 0 |
| 38458188 | 2024 | SMARCA4 is a haploinsufficient B cell lymphoma tumor suppressor that fine-tunes centrocyte cell fate decisions. | 1 |
| 38552892 | 2024 | Deciphering the role of SMARCA4 in cardiac disorders: Insights from single-cell studies on dilated cardiomyopathy and coronary heart disease. | 0 |
| 38642845 | 2024 | SMARCA4 (BRG1) activates ABCC3 transcription to promote hepatocellular carcinogenesis. | 0 |
| 38688602 | 2024 | ARID1 and BRG1 Expression in Endometrial Cancer. | 0 |
| 38763102 | 2024 | Rare SMARCA4-deficient thoracic tumor: Insights into molecular characterization and optimal therapeutics methods. | 0 |
| 38840387 | 2024 | ATP-dependent chromatin remodeller brahma related gene 1 promotes keratinocyte migration and modulates cell Signalling during wound healing in human skin. | 0 |
| 38877473 | 2024 | Gastric SMARCA4-deficient undifferentiated tumor (SMARCA4-UT): a clinicopathological analysis of four rare cases. | 0 |
Citation
Pedro P Medina ; Montse Sanchez-Cespedes, PhD
SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4)
Atlas Genet Cytogenet Oncol Haematol. 2008-04-01
Online version: http://atlasgeneticsoncology.org/gene/42333
