SWI/SNF and Cancer Human
SWI/SNF are approximately 2 MDa complexes composed of 12-15 subunits. There are three distinct mature complexes―BAF (BRG1-associated factor), PBAF (polybromo BRG1-associated factor) and ncBAF (non-canonical). These complexes contain one of the two catalytic ATPase subunits, SMARCA4 (BRG1) or SMARCA2 (BRM,) several core subunits including SMARCC1 (BAF155) and SMARCD1, as well as unique subunits such as ARID1A/B for BAF, and PBRM1 and ARID2 specific for PBAF and GLTSCR1 and BRD9 for ncBAF varieties of the complexes. Genes encoding many subunits of SWI/SNF complexes have been found to be recurrently mutated in 20% of all human cancers. Multiple subunits are mutated in a wide spectrum of cancers, emphasizing that individual subunits are important in varying cell types and lineages. Hence an understanding of the mechanism by which SWI/SNF regulates transcription and the effect of mutations on proper SWI/SNF function will be important for improved cancer therapy.
Paralogous subunits and their redundancy
From a therapeutic standpoint, as mutations in genes encoding SWI/SNF complex subunits are often loss-of-function, including nonsense, frameshift, and large deletions, the products of the mutant genes themselves do not constitute obvious drug targets. Consequently, it is of great interest to identify specific vulnerabilities conferred by these mutations upon cancer cells that have the potential to provide new therapeutic opportunities. One of the critical interests in this context is identification of synthetic lethality in SWI/SNF complex, owing to the many paralogous subunits it contains.
ARID1A and ARID1B are 60% identical in protein sequence and are mutually exclusive since individual SWI/SNF chromatin remodeling complexes can contain either ARID1A or ARID1B but not both. In ARID1A mutant cancer cells, ARID1B was identified as the number one dependency, suggesting that ARID1A mutation, cells become reliant upon ARID1B. Same is the case with ATPases, cells with SMARCA4 mutation rely on SMARCA2 as the remaining SWI/SNF ATPase subunit and thus cannot tolerate loss of SMARCA2 residual complex. The mechanism by which these residual complexes contribute to tumorigenesis is not yet fully understood. One way we can begin to understand is by deciphering the exact redundant and nonredundant functions of these paralogs.
In this context as ARID1A and SMARCA4 are the most frequently mutated subunit known across many cancers we are interested to understand how different they are from their paralogs ARID1B and SMARCA2 respectively. We are also focused on the role of acetylation of SMARCA2 as we have previously found important functions of acetylation of its yeast homolog, Snf2. Yeast Snf2 targets acetylated nucleosomes through its bromodomain which binds acetyl-lysine. However, when the SAGA complex acetylates the Snf2 protein itself the bromodomain binds to acetyl-lsyines on Snf2 releasing it from the acetylated nucleosomes.