PRPF19 is a multifunctional ubiquitin-protein ligase with dual roles in pre-mRNA splicing and DNA damage response. As a core component of the spliceosome's PRP19C/Prp19 complex, PRPF19 mediates Lys-63-linked polyubiquitination of spliceosomal proteins like PRPF3, stabilizing the U4/U5/U6 tri-snRNP complex and enabling proper spliceosome assembly and activity 1. In DNA repair, PRPF19 is recruited to damage sites where it ubiquitinates RPA complex proteins, facilitating ATR-mediated DNA damage checkpoint activation 2. PRPF19 participates in topoisomerase complex assembly critical for genome stability 3. Clinically, pathogenic PRPF19 variants cause neurodevelopmental disorders through splicing dysregulation, with neural loss-of-function producing lethality and brain abnormalities in model organisms 4. PRPF19 upregulation associates with poor prognosis in cancers including high-grade serous ovarian cancer and prostate cancer, where it promotes proliferation, migration, and chemoresistance while suppressing autophagy 56. Conversely, PRPF19 knockdown enhanced chemosensitivity and reduced tumor growth. PRPF19 is implicated in ferroptosis regulation through VDR degradation in diabetic nephropathy 7, while overexpression promotes skin cell viability and slows aging 8. These studies establish PRPF19 as a therapeutic target across multiple pathologies.