POLD4 is the smallest accessory subunit of the tetrameric DNA polymerase delta complex, essential for high-fidelity genome replication and repair 1. Within Pol-delta4, POLD4 increases DNA synthesis rates and regulates POLD1 polymerase and proofreading activity, participating in Okazaki fragment processing and translesion synthesis of damaged DNA templates 2. Under replication stress, POLD4 is required for break-induced replication (BIR) repair and interacts with PCNA via a non-canonical PIP motif to facilitate polymerase processivity 3. POLD4 degradation following DNA damage is critical for inhibiting fork progression and promoting cell survival. Clinically, POLD4 is significantly upregulated in glioblastoma and associated with poor overall survival, disease-free survival, and progression-free survival 4. In glioma stem cells, the deubiquitinase UCHL3 stabilizes POLD4, conferring radiation resistance through enhanced homologous recombination and non-homologous end joining repair; UCHL3 inhibition enhances radiation therapy efficacy 5. POLD4 expression correlates with inflammatory pathways, epithelial-mesenchymal transition, and suppressive immune microenvironments across multiple cancer types 6. POLD4 reduction impairs cell proliferation and induces genomic instability in human cells, suggesting its role in maintaining chr11 integrity 2.