Biology:ARID1A

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Short description: Protein-coding gene in humans

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

AT-rich interactive domain-containing protein 1A is a protein that in humans is encoded by the ARID1A gene.[1][2][3]

Function

ARID1A is a member of the SWI/SNF family, whose members have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodelling complex SWI/SNF, which is required for transcriptional activation of genes normally repressed by chromatin. The protein has two large intrinsically disordered regions (IDRs) that mediate the interaction with binding partners.[4] It also possesses at least two conserved domains that are important for its function. First, it has an ARID domain, which is a DNA-binding domain that can specifically bind an AT-rich DNA sequence known to be recognized by a SWI/SNF complex at the beta-globin locus. Second, the C-terminus of the protein can stimulate glucocorticoid receptor-dependent transcriptional activation. The protein encoded by this gene confers specificity to the SWI/SNF complex and recruits the complex to its targets through either protein-DNA or protein-protein interactions.[5][6] Two transcript variants encoding different isoforms have been found for this gene.[3]

Clinical significance

The gene encoding ARID1A is the most frequently mutated SWI/SNF subunit across cancers.[7] This gene has been commonly found mutated in different cancers leading to loss of function, including gastric cancers,[8] colon cancer,[9] ovarian clear cell carcinoma,[10] liver cancer,[11] lymphoma[5] and pancreatic cancer.[12] In breast cancer distant metastases acquire inactivation mutations in ARID1A not seen in the primary tumor, and reduced ARID1A expression confers resistance to different drugs such as trastuzumab and mTOR inhibitors. These findings provide a rationale for why tumors accumulate ARID1A mutations.[13][14]

Research

Lack of this gene/protein seems to protect rats from some types of liver damage.[15]

Interactions

ARID1A interacts with SWI/SNF subunits SMARCB1[16][17] and SMARCA4.[17][18] Intrinsically disordered regions of ARID1A enable the SWI/SNF complex to interact with multiple transcription factors through binding of the ARM domain of beta-catenin.[4]

References

  1. ↑ "Chromosomal mapping and expression of the human B120 gene". Gene 213 (1–2): 189–193. June 1998. doi:10.1016/S0378-1119(98)00194-2. PMID 9630625. 
  2. ↑ "Molecular cloning and expression of a novel human cDNA containing CAG repeats". Gene 204 (1–2): 71–77. December 1997. doi:10.1016/S0378-1119(97)00525-8. PMID 9434167. 
  3. ↑ 3.0 3.1 "Entrez Gene: ARID1A AT rich interactive domain 1A (SWI-like)". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=8289. 
  4. ↑ 4.0 4.1 "β-catenin functions as a molecular adapter for disordered cBAF interactions". Molecular Cell 85 (16): S1097–2765(25)00576–3. 2025-07-15. doi:10.1016/j.molcel.2025.06.026. ISSN 1097-4164. PMID 40695292. 
  5. ↑ 5.0 5.1 "ARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis". Cancer Cell 42 (4): 583–604.e11. March 2024. doi:10.1016/j.ccell.2024.02.010. PMID 38458187. 
  6. ↑ "A disordered region controls cBAF activity via condensation and partner recruitment". Cell 186 (22): 4936–4955.e26. October 2023. doi:10.1016/j.cell.2023.08.032. PMID 37788668. 
  7. ↑ "Context-specific functions of chromatin remodellers in development and disease". Nature Reviews. Genetics 25 (5): 340–361. November 2023. doi:10.1038/s41576-023-00666-x. PMID 38001317. 
  8. ↑ "Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer". Nature Genetics 43 (12): 1219–1223. October 2011. doi:10.1038/ng.982. PMID 22037554. 
  9. ↑ "ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice". Nature Genetics 49 (2): 296–302. February 2017. doi:10.1038/ng.3744. PMID 27941798. 
  10. ↑ "ARID1A mutations in endometriosis-associated ovarian carcinomas". The New England Journal of Medicine 363 (16): 1532–1543. October 2010. doi:10.1056/NEJMoa1008433. PMID 20942669. 
  11. ↑ "Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer". Cancer Cell 32 (5): 574–589.e6. November 2017. doi:10.1016/j.ccell.2017.10.007. PMID 29136504. 
  12. ↑ "Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer". Proceedings of the National Academy of Sciences of the United States of America 109 (5): E252–E259. January 2012. doi:10.1073/pnas.1114817109. PMID 22233809. Bibcode: 2012PNAS..109E.252S. 
  13. ↑ "Loss of ARID1A Activates ANXA1, which Serves as a Predictive Biomarker for Trastuzumab Resistance". Clinical Cancer Research 22 (21): 5238–5248. November 2016. doi:10.1158/1078-0432.CCR-15-2996. PMID 27172896. 
  14. ↑ "Genomic Evolution of Breast Cancer Metastasis and Relapse". Cancer Cell 32 (2): 169–184.e7. August 2017. doi:10.1016/j.ccell.2017.07.005. PMID 28810143. 
  15. ↑ "Tissue Regeneration Promoted through Gene Suppression". Genetic Engineering & Biotechnology News. March 2016. http://www.genengnews.com/gen-news-highlights/tissue-regeneration-promoted-through-gene-suppression/81252529/. 
  16. ↑ "SYT associates with human SNF/SWI complexes and the C-terminal region of its fusion partner SSX1 targets histones". The Journal of Biological Chemistry 277 (7): 5498–5505. February 2002. doi:10.1074/jbc.M108702200. PMID 11734557. 
  17. ↑ 17.0 17.1 "Purification and biochemical heterogeneity of the mammalian SWI-SNF complex". The EMBO Journal 15 (19): 5370–5382. October 1996. doi:10.1002/j.1460-2075.1996.tb00921.x. PMID 8895581. 
  18. ↑ "Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling". Cell 95 (5): 625–636. November 1998. doi:10.1016/S0092-8674(00)81633-5. PMID 9845365. 

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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