SWI/SNF chromatin remodelers, DNA repair, transcription, and cancer therapy

SWI/SNF ATP-dependent chromatin remodelers are large multi-subunit complexes responsible for modulating chromatin accessibility for various processes such as transcription and DNA repair. Various subunits within these complexes are mutated in up to 20% of human cancers and thus have important tumor suppressor functions. SWI/SNF chromatin remodelers hydrolyze ATP to position nucleosomes along the DNA and reorganize chromatin structure. There are three main SWI/SNF complexes in somatic mammalian cells known as the canonical BAF (cBAF, canonical BRG1-associated factor), PBAF (polybromo BRG1-associated factor), and ncBAF (noncanonical BRG1-associated factor). These complexes contain one of two mutually exclusive ATPases, BRG1 or BRM. While these two ATPases share high sequence identity, they have overlapping and distinct roles. In addition to the ATPases, these complexes share several core factors and contain characteristic accessory subunits that differentiate them from each other. While the function of the ATPases is clear, the function and potential role(s) of other subunits within the function(s) of SWI/SNF is less clear. The link between SWI/SNF complexes and cancer is well established. Earlier studies regarding SWI/SNF complexes focused on how mutations in specific subunits resulted in particular cancer types. More recent work has identified novel functions for these complexes in a variety of aspects of cancer that not only are important for cancer development, but rather that can be exploited to develop therapies . For instance, we have now identified cancers that are “addicted” to SWI/SNF and thus require SWI/SNF activity for their survival. Similarly, we have also identified novel roles for SWI/SNF in the repair of DNA double strand breaks (DSBs) and thus we know that some SWI/SNF-mutated cancers have a DNA repair vulnerability that can be exploited therapeutically as these cancers are sensitive to particular types of chemotherapy. Various studies have also linked SWI/SNF to the activation of the cGAS/STING pathway in response to DNA damage and the activation of this immune response is associated with better therapy outcomes and a positive response to immune blockade therapy. The goal of this Research Topic is to describe recent advances in the SWI/SNF chromatin remodeling field that can help in the development of cancer therapies. Given the importance of SWI/SNF chromatin remodelers in normal development, in the development of cancer, and more recently identified role that these complexes play in cancer cell survival and genome stability, this collection seeks to describe different aspects of SWI/SNF function that can be exploited therapeutically against cancer. The recent development of small molecule inhibitors against SWI/SNF ATPases, bromodomains, and the development of protein targeting chimeras (PROTACs) that induce the degradation of various SWI/SNF subunits have been shown to be important tools not only for the identification of new functions and mechanisms of SWI/SNF chromatin remodeling, but also for the treatment of cancer. These tools can be used to target specific cancer types, SWI/SNF-mutated cancers, or to sensitize cancer cells to chemotherapy. We welcome original research, reviews, and perspectives that explore the underlying pathways, identify tumor-specific vulnerabilities, and evaluate how targeting SWI/SNF-dependent mechanisms could inform novel combinatorial cancer therapies. Contributions that highlight therapeutic implications and translational advances are particularly encouraged. Topic editors: Renier Velez-Cruz, Sandipan Brahma Source: https://www.frontiersin.org/research-topics/72328/swisnf-chromatin-remodelers-dna-repair-transcription-and-cancer-therapy