The Role of SWI/SNF Chromatin Re­modelers in Homologous Recombination and Genome Stability

This review synthesizes current understanding of how SWI/SNF chromatin remodeling complexes function in the repair of DNA double-strand breaks (DSBs) and the implications of that function for cancer therapy. SWI/SNF complexes, also known as Switch/Sucrose non-fermenting complexes, use ATP hydrolysis to reposition nucleosomes and thereby modulate DNA accessibility. While historically characterized for roles in transcription regulation, recent work summarized in this review highlights a distinct and clinically relevant role for SWI/SNF in DSB repair, with a particular emphasis on homologous recombination (HR).

The authors describe the three primary forms of SWI/SNF complexes in somatic mammalian cells—canonical BAF (cBAF), polybromodomain BAF (PBAF), and non-canonical BAF (ncBAF)—noting that these complexes can include either the BRG1 or BRM ATPase as the catalytic motor. cBAF and PBAF contain a core group of subunits (BAF47, BAF57, BAF60, BAF155, BAF170) and various accessory factors, while ncBAF contains a reduced core. PBAF uniquely contains polybromodomain proteins PBRM1 (BAF180) and BRD7, and ncBAF contains BRD9. The review points out that many SWI/SNF subunits are recurrently mutated in diverse human cancers, and it presents data on mutation frequency across tumor types drawn from TCGA Pan-Cancer Atlas analyses. Domain structures of key ATPases, BRG1 and BRM, are discussed, describing domains such as QLQ, HSA, the ATPase/helicase core, SnAC, A-T hook motifs, and bromodomains. ARID-containing subunits (ARID1A, ARID1B, ARID2) and bromodomain-containing proteins (PBRM1, BRD7, BRD9) are also profiled regarding their domain architecture.

Central to the review is the connection between SWI/SNF function in DNA end resection and HR-mediated repair of DSBs. Since radiotherapy and many chemotherapies exert cytotoxicity primarily through the induction of DSBs, the involvement of SWI/SNF complexes in DSB repair reveals potential therapeutic vulnerabilities in cancers harboring SWI/SNF mutations. The authors discuss how defects in SWI/SNF subunits could sensitize tumors to specific DNA damage response-targeting agents, including PARP inhibitors, by compromising homologous recombination or other repair pathways.

Throughout, the review emphasizes translational implications: understanding which SWI/SNF subunits are altered in particular cancers and how those alterations affect chromatin remodeling at break sites could guide the rational combination of DNA-damaging therapies with agents that exploit repair defects. Vélez-Cruz and colleagues present a consolidated view of molecular mechanistic studies, mutation landscape analyses, and therapeutic considerations, framing SWI/SNF complexes both as fundamental chromatin regulators and as determinants of genome stability with direct relevance to cancer treatment strategies. This synthesis aims to inform future investigation into targeted therapies that leverage SWI/SNF-associated DNA repair vulnerabilities.