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Mutations in SWI/SNF genes are amongst the most common across all human cancers, but efficient therapeutic approaches that exploit vulnerabilities caused by SWI/SNF mutations are currently lacking. Here, we show that the SWI/SNF ATPases BRM/SMARCA2 and BRG1/SMARCA4 promote the expression of p62/GTF2H1, a core subunit of the transcription factor IIH (TFIIH) complex. Inactivation of either ATPase subunit downregulates GTF2H1 and therefore compromises TFIIH stability and function in transcription and nucleotide excision repair (NER). We also demonstrate that cells with permanent BRM or BRG1 depletion have the ability to restore GTF2H1 expression. As a consequence, the sensitivity of SWI/SNF-deficient cells to DNA damage induced by UV irradiation and cisplatin treatment depends on GTF2H1 levels. Together, our results expose GTF2H1 as a potential novel predictive marker of platinum drug sensitivity in SWI/SNF-deficient cancer cells., SWI/SNF genes are commonly found to be mutated in different cancers. Here the authors report that the remodelers BRM and BRG1 are necessary for efficient nucleotide excision repair by promoting the expression of TFIIH subunit GTF2H1.

The SWI/SNF complex is a chromatin-remodeling complex that uses the energy of ATP hydrolysis to modify chromatin structure in order to regulate gene expression. The SWI/SNF complex is evolutionarily conserved in all eukaryotes and is comprised of a catalytic subunit, either of BRG1 (also known as SMARCA4) or of BRM (also known as SMARCA2), and a variety of associated proteins that can modulate the recruitment of the complex and its activity. Key observations link the SWI/SNF complex with cancer. First, two of its subunits (SNF5 and BRG1) bear cancer-inactivating mutations and thus are bona fide tumor suppressors. The SNF5 gene is biallelically inactivated in malignant rhabdoid tumors (MRTs) whereas BRG1 is mutated in cancer cell lines of several types, such as those of the breast, prostate, lung, pancreas and colon. Second, mice heterozygous for mutations at Snf5 and Brg1 are cancer-prone, and, third, BRG1 binds or is related to important tumor-suppressor proteins. The present review focuses on the biological function and genetics of BRG1, particularly with respect to its role as a tumor suppressor.

Background: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients’ quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown. Experimental Design and Results: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before; albeit most frequent mutations were found in ARID1A, ARID2 and BRAF. Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation.

RNA helicases are essential for virtually all cellular processes, however, their regulation is poorly understood. The activities of eight RNA helicases are required for pre-mRNA splicing. Amongst these, Brr2p is unusual in having two helicase modules, of which only the amino-terminal helicase domain appears to be catalytically active. Using genetic and biochemical approaches, we investigated interaction of the carboxy-terminal helicase module, in particular the carboxy-terminal Sec63-2 domain, with the splicing RNA helicase Prp16p. Combining mutations in BRR2 and PRP16 suppresses or enhances physical interaction and growth defects in an allele-specific manner, signifying functional interactions. Notably, we show that Brr2p Sec63-2 domain can modulate the ATPase activity of Prp16p in vitro by interfering with its ability to bind RNA. We therefore propose that the carboxy-terminal helicase module of Brr2p acquired a regulatory function that allows Brr2p to modulate the ATPase activity of Prp16p in the spliceosome by controlling access to its RNA substrate/cofactor.

Mutations in genes that encode proteins of the SWI/SNF complex, called BAF complex in mammals, cause a spectrum of disorders that ranges from syndromic intellectual disability to Coffin-Siris syndrome (CSS) to Nicolaides-Baraitser syndrome (NCBRS). While NCBRS is known to be a recognizable and restricted phenotype, caused by missense mutations in SMARCA2, the term CSS has been used lately for a more heterogeneous group of phenotypes that are caused by mutations in either of the genes ARID1B, ARID1A, ARID2, SMARCA4, SMARCB1, SMARCE1, SOX11, or DPF2. In this review, we summarize the current knowledge on the phenotypic traits and molecular causes of the above named conditions, consider the question whether a clinical distinction of the phenotypes is still adequate, and suggest the term "SWI/SNF-related intellectual disability disorders" (SSRIDDs). We will also outline important features to identify the ARID1B-related phenotype in the absence of classic CSS features, and discuss distinctive and overlapping features of the SSRIDD subtypes. Moreover, we will briefly review the function of the SWI/SNF complex in development and describe the mutational landscapes of the genes involved in SSRIDD.