DEFINING THE ROLE OF THE PCGF3-CONTAINING POLYCOMB REPRESSIVE COMPLEX 1 IN SYNOVIAL SARCOMA

Synovial Sarcoma (SS) poses significant challenges in diagnosis and treatment due to its rarity and therapeutic options. The fusion protein SS18-SSX, found in over 95% of cases, is considered the primary oncogenic driver, disrupting BAF complexes and redirecting them to Polycomb repressive domains, thus activating them. This mislocalization depends on the higher affinity of the fusion oncoprotein for H2AK119ub, the histone modification deposited by Polycomb Repressive Complex 1 (PRC1). However, the precise molecular mechanisms underlying SS18-SSX transformation remain unclear. Given SS's disruption of epigenetic regulators SWI/SNF and Polycomb complexes, my study aims to uncover genetic vulnerabilities within these networks driving SS proliferation. Through a meticulous analysis on the Depmap portal, I identified PCGF3, a key component of PRC1.3, as a robust synthetic lethality hit specific to SS. Employing cutting-edge techniques like CRISPR/Cas9 and the dTAG system, I meticulously investigated the molecular mechanisms underpinning PCGF3's synthetic lethality, focusing on its strong catalytic activity. My research seeks to unravel the intricate molecular mechanisms dictating SS proliferation, offering insights with significant clinical implications. Understanding these pathways may pave the way for targeted therapeutic interventions, addressing the urgent need for effective treatments in SS management.