The human genome encodes only about 23,000 genes but over 100,000 proteins. This immense diversity of protein expression, in spite of a finite number of coding genes, is achieved through alternative splicing and processing of pre-mRNA transcripts. It is estimated that over 93% of human genes undergo alternative splicing. This process is critical for the proper expression of many genes across a wide variety of pathways. Not surprisingly, this pathway is deregulated in at least 15% of human diseases, including myelodysplastic syndrome, autism-spectrum disorders, amyotrophic lateral sclerosis (ALS), and cancer. While the core spliceosomal machinery is known, there are a large number of associated regulatory factors whose identity and function are still unclear. One of these associated specificity controllers is the SWI/SNF complex, which has recently been implicated in the control of pre-mRNA splicing. SWI/SNF is an ATP-dependent nucleosome-remodeling complex conserved from yeast to mammals. In flies and vertebrates the complex is involved in development, differentiation, and is essential for the establishment and maintenance of embryonic stem cells. The SWI/SNF complex contains 11-12 tumor suppressor subunits which have been found to be frequently mutated in a wide variety of adult and pediatric cancers. Recently, an analysis across 44 exome studies found that 20% of primary human cancers had mutations in SWI/SNF members, approaching the mutation rate of p53, the most frequently mutated tumor suppressor gene in cancer. However, the mechanisms of how mutations in this complex drive cancer remain largely unclear. Changes in SWI/SNF splicing after mutation of the complex may be part of the oncogenesis of these cancers. This proposal will elucidate the mechanisms of SWI/SNF splicing and the contribution of SWI/SNF splicing to cancer. This will be done in the following two aims: 1) Determine the effects of SWI/SNF mutation on splicing outcome, dependencies on splicing factors, and nucleosome remodeling at target genes 2) Determine the composition of the SWI/SNF splicing complex and whether it associates with known splicing factors to effect the splicing of targets. These studies will enhance the understanding of pre-mRNA splicing and how disruption of this process can contribute to disease. Understanding how the SWI/SNF complex is involved in splicing will provide insights into the mechanisms of malignancy in the wide spectrum of cancers in which this complex is mutated. This proposal also will further the understanding of splicing regulation and how this intricate process is controlled.
Twenty percent of human cancers have mutations in the SWI/SNF protein complex. This complex functions in the nucleus to control the expression and specificity of genes. This project will elucidate the mechanisms of this regulation and provide insights into cancer growth.
