SWI/SNF complex

Functions

SWI/SNF chromatin remodeling ATPases control accessibility of the information stored in the genome. However, the in vivo role of these remodelers has remained poorly understood because null mutations in these result in embryonic lethality in most organisms.

Swi/Snf activates transcription by remodeling nucleosomes, thereby permitting increased access of transcription factors for their binding sites.

Nucleosome remodeling complexes modify chromatin topology in an ATP-dependent manner by disrupting DNA-histone interactions. They thereby facilitating sliding of the nucleosome, and hence the accessibility of the DNA to transcription factors.

The SWI/SNF complex regulates genes locally, and analyses of yeast SWI/SNF mutants revealed that transcription of 5% of all yeast genes is influenced by SWI/SNF mutations.

The SWI/SNF core complex consists of SNF5/INI1, BRG1, BRM, BAF155, and BAF170. SWI/SNF interacts with many protein complexes central to cancer development, such as RB, p53, MYC, MLL, BRCA1, and beta-catenin; hence, functional inactivation of SWI/SNF impinges on a multitude of cellular growth control pathways.

Analyses of the SWI/SNF core subunit SNF5 (INI1) have revealed the presence of inactivating mutations in highly aggressive human malignant rhabdoid tumors. SNF5 mutations are underlying familial cancers in which one SNF5 allele carries a germ-line mutation and the other allele is lost during tumorigenesis.

The tumor-suppressive effect of SNF5 is evident from the fact that reintroduction of SNF5 into SNF5-mutant tumor cells mediates cell cycle arrest and from mouse models demonstrating Snf5 as a haploinsufficient tumor-suppressor gene, complete loss of which causes mice to succumb early in life to aggressive lymphomas or rhabdoid tumors.

Components

SMARCA1

SMARCA2

SMARCA3

SMARCA4

SMARCB1

Pathology

 SMARCB1 (SNF5/INI1)

• somatic SMARCB1 (SNF5/INI1) mutations in rhabdoid tumor (MIM.609322)
• germline SMARCB1 mutations in rhabdoid tumor predisposing syndrome (MIM.609322)

 SMARCA4

• somatic mutation of SMARCA4 in lung carcinoma (15%) (15287030)
• germline mutations of SMARCA4 in rhabdoid tumor predisposing syndrome (MIM.609322)

 SWI/SNF complex-deficient undifferentiated/rhabdoid carcinomas of the gastrointestinal Tract (26551623)

Reviews

 The SWI/SNF complex and cancer. Reisman D, Glaros S, Thompson EA. Oncogene. 2009 Apr 9;28(14):1653-68. PMID: 19234488

 Kwon CS, Wagner D. Unwinding chromatin for development and growth: a few genes at a time. Trends Genet. 2007 Aug;23(8):403-12. PMID: 17566593

 Lund AH, van Lohuizen M. Epigenetics and cancer. Genes Dev. 2004 Oct 1;18(19):2315-35. PMID: 15466484 (free)

 Gibbons RJ. Histone modifying and chromatin remodelling enzymes in cancer and dysplastic syndromes. Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R85-92. PMID: 15809277

 Roberts CW, Orkin SH. The SWI/SNF complex - chromatin and cancer. Nat Rev Cancer. 2004 Feb;4(2):133-42. PMID: 14964309

 Klochendler-Yeivin A, Yaniv M. Chromatin modifiers and tumor suppression. Biochim Biophys Acta. 2001 Aug 31;1551(1):M1-10. PMID: 11553416

 Muchardt C, Yaniv M. When the SWI/SNF complex remodels...the cell cycle. Oncogene. 2001 May 28 ;20(24):3067-75. PMID : 11420722

 Muchardt C, Yaniv M. The mammalian SWI/SNF complex and the control of cell growth. Semin Cell Dev Biol. 1999 Apr ;10(2):189-95. PMID : 10441072

 Sudarsanam P, Winston F. The Swi/Snf family nucleosome-remodeling complexes and transcriptional control. Trends Genet. 2000 Aug;16(8):345-51. PMID: 10904263

References

 SWI/SNF Complex-deficient Undifferentiated/Rhabdoid Carcinomas of the Gastrointestinal Tract: A Series of 13 Cases Highlighting Mutually Exclusive Loss of SMARCA4 and SMARCA2 and Frequent Co-inactivation of SMARCB1 and SMARCA2. Agaimy A, Daum O, Märkl B, Lichtmannegger I, Michal M, Hartmann A. Am J Surg Pathol. 2015 Nov 5. PMID: 26551623