"PROJECT SUMMARY/ ABSTRACT Modern genome-wide sequencing efforts have revealed unexpectedly high mutation frequencies in the genes encoding chromatin regulators and modifiers, which are implicated in several diseases including cancer and developmental disorders. One family of chromatin regulators include the mSWI/SNF (BAF) family of ATP- dependent chromatin remodeling complexes, which regulate the structure of the genome and are essential for timely and appropriate gene expression. mSWI/SNF complex mutations have been identified in approximately 20% of all cancers, underscoring the need for mechanistic investigation critical to improve our understanding and treatment of cancer. The mSWI/SNF complexes are comprised of a core ATPase subunit, BRG1 or BRM, additional core subunits, BAF155, BAF170, and BAF47, and a variety of interchangeable subunits that are thought to provide distinct roles in attenuating BAF complex activity. Homozygous loss of the SMARCB1 gene (coding for BAF47) results in the development of malignant rhabdoid tumor (MRT), one of the most aggressive and lethal pediatric cancers, however the underlying mechanisms by which BAF47 loss drives oncogenesis is not understood. Given that BAF47 is highly conserved between mammals to yeast (SNF5), I hypothesize that the loss of the core BAF47 subunit destabilizes the recruitment of additional subunits on BAF complexes, thereby decreasing BAF complex structural integrity. Furthermore, I predict that BAF47 loss redirects BAF complexes genome-wide, yielding altered transcriptional activity, and ultimately resulting in cell cycle de-regulation implicit in cancer. In an effort to examine these hypotheses, this project will: (Aim 1) Determine the role of BAF47 in dictating BAF complex stability and composition, and identify regions of BAF47 responsible for complex incoporation and tethering of other BAF complex subunits; and (Aim 2) Determine the role of BAF47 in BAF complex targeting genome-wide, global gene expression, and assess synthetic lethality of identified target genes. Upon successful completion of these investigations, we will gain a more comprehensive mechanistic understanding of the contribution of BAF47 to BAF complex stability and activity as well as the role of BAF47 loss in the development of MRT. This information would also inform our understanding of general BAF complex activity and its role in other diseases." |