POLDIP3 (DNA polymerase delta interacting protein 3) is a multifunctional protein involved in DNA replication stress responses and mRNA processing regulation. POLDIP3 associates with RTEL1 helicase to facilitate replication stress responses and R-loop resolution, with loss of either protein leading to marked R-loop accumulation at active replication sites and genomic instability 1. The protein functions as an antiviral factor, as demonstrated by its ability to inhibit coronavirus infection, while viral nsp5 proteases counteract this by cleaving POLDIP3 at glutamine 176, facilitating viral replication 2. POLDIP3 serves as a transcriptional target of TDP-43, with TDP-43 loss-of-function leading to defective splicing of POLDIP3 in ALS models, contributing to disease pathogenesis 3. An alternative splice variant lacking exon 3 (POLDIP3-β) is upregulated in hepatocellular carcinoma and promotes tumor progression through enhanced proliferation, reduced apoptosis, and increased migration 4. POLDIP3 has been identified as a component of the human TREX complex involved in mRNA export, though its direct interaction with viral proteins like ORF57 remains unclear 5. The protein's diverse functions span DNA replication fidelity, antiviral immunity, and cancer progression, making it a significant target for therapeutic intervention.