In molecular biology, SWI/SNF (SWItch/Sucrose Non-Fermentable), is a subfamily of ATP-dependent chromatin remodeling complexes, which is found in eukaryotes. In other words, it is a group of proteins that associate to remodel the way DNA is packaged. This complex is composed of several proteins – products of the SWI and SNF genes (, /, , , ), as well as other polypeptides. It possesses a DNA-stimulated ATPase activity that can destabilize histone-DNA interactions in reconstituted nucleosomes in an ATP-dependent manner, though the exact nature of this structural change is unknown. The SWI/SNF subfamily provides crucial nucleosome rearrangement, which is seen as ejection and/or sliding. The movement of nucleosomes provides easier access to the chromatin, allowing genes to be activated or repressed.
The human analogs of SWI/SNF are "BRG1- or BRM-associated factors", or BAF (SWI/SNF-A) and "Polybromo-associated BAF", which is also known as PBAF (SWI/SNF-B). There are also Drosophila analogs of SWI/SNF, known as "Brahma Associated Protein", or BAP and "Polybromo-associated BAP", also known as PBAP.
Mechanism of action
It has been found that the SWI/SNF complex (in yeast) is capable of altering the position of nucleosomes along DNA. These alterations are classified in three different ways, and they are seen as the processes of sliding nucleosomes, ejecting nucleosomes, and ejecting only certain components of the nucleosome. Due to the actions performed by the SWI/SNF subfamily, they are referred to as "access remodellers" and promote gene expression by exposing binding sites so that transcription factors can bind more easily. Two mechanisms for nucleosome remodeling by SWI/SNF have been proposed. The first model contends that a unidirectional diffusion of a twist defect within the nucleosomal DNA results in a corkscrew-like propagation of DNA over the octamer surface that initiates at the DNA entry site of the nucleosome. The other is known as the "bulge" or "loop-recapture" mechanism and it involves the dissociation of DNA at the edge of the nucleosome with re-association of DNA inside the nucleosome, forming a DNA bulge on the octamer surface. The DNA loop would then propagate across the surface of the histone octamer in a wave-like manner, resulting in the re-positioning of DNA without changes in the total number of histone-DNA contacts. A recent study has provided strong evidence against the twist diffusion mechanism and has further strengthened the loop-recapture model.
Role as a tumor suppressor
The mammalian SWI/SNF (mSWI/SNF) complex functions as a tumor suppressor in many human malignant cancers. Early studies identified that SWI/SNF subunits were frequently absent in cancer cell lines. SWI/SNF was first identified in 1998 as a tumor suppressor in rhabdoid tumors, a rare pediatric malignant cancer. Other instances of SWI/SNF acting as a tumor suppressor comes from the heterozygous deletion of BAF47 or alteration of BAF47. These instances result in cases of chronic and acute CML and in rarer cases, Hodgkin's lymphoma, respectively. To prove that BAF47, also known as SMARCB1, acts as a tumor suppressor, experiments resulting in the formation of rhabdoid tumors in mice were conducted via total knockout of BAF47. As DNA sequencing costs diminished, many tumors were sequenced for the first time around 2010. Several of these studies revealed SWI/SNF to be a tumor suppressor in a number of diverse malignancies. Several studies revealed that subunits of the mammalian complex, including ARID1A, PBRM1, SMARCB1, SMARCA4, and ARID2, are frequently mutated in human cancers. It has been noted that total loss of BAF47 is extremely rare and instead, most cases of tumors that resulted from SWI/SNF subunits come from BRG1 deletion, BRM deletion, or total loss of both subunits. Further analysis concluded that total loss of both subunits was present in about 10% of tumor cell lines after 100 cell lines were looked at. A meta-analysis of many sequencing studies demonstrated SWI/SNF to be mutated in approximately 20% of human malignancies.