Project Abstract Pancreatic cancer is one of the most lethal types of cancer worldwide. Less than 7% of patients survive this deadly disease. Despite efforts, few effective therapies exist. Intriguingly, the methyltransferase PRMT5 has been identified as a cancer dependency in MTAP null tumors, which constitute 15% of all tumors and 30% of pancreatic ductal adenocarcinomas. Therefore, PRMT5 is an attractive target in pancreatic cancer. This PRMT5 dependency arises due to the passenger deletion of the MTAP gene that is adjacent to the frequently deleted tumor suppressor gene CDKN2A on chromosome 9. In tumors lacking MTAP, its substrate, methylthioadenosine (MTA) accumulates and competitively inhibits the PRMT5 enzyme.!While therapeutic targeting of PRMT5 has focused on targeting the catalytic pocket, our preliminary studies demonstrate a novel and potentially important face of the PRMT5 methylosome that may overcome cellular specificity and efficacy issues with PRMT5 catalytic inhibitors. Therefore, I hypothesize that the newly identified PRMT5-substrate adaptor interface is required for PRMT5 activity and is thus essential for the growth of MTAP null tumors. Through the following two Aims, we will address whether the PRMT5-substrate adaptor site is required for all or particular PRMT5 functions and establish whether disruption of this protein interaction site might have a therapeutic benefit in pancreatic cancer.