POLDIP2 is a multifunctional adaptor protein with dual roles in DNA damage tolerance and oxidative stress regulation. As a primary function, POLDIP2 regulates translesion synthesis (TLS) by stimulating DNA polymerases involved in bypassing DNA lesions, particularly PRIMPOL and polymerase delta (POLD1) 1. POLDIP2 enhances PrimPol's polymerase activity and processivity while promoting error-free bypass of 8-oxoG lesions 2. Mechanistically, POLDIP2 possesses a compact two-domain structure with DUF525 and YccV domains, featuring a central channel and dynamic N-terminal region that facilitates interactions with multiple binding partners 3. Beyond DNA repair, POLDIP2 functions as a regulator of oxidative stress through interaction with NADPH oxidase 4 (Nox4), acting as an upstream regulator of ROS production via PI3K-AKT signaling 4. Clinically, POLDIP2 has emerged as a significant AMD-risk gene 5, with evidence implicating it in diabetic retinopathy pathology through both oxidative stress mechanisms and TGF-β1/SMAD3-mediated retinal fibrosis 67. Additionally, POLDIP2 inhibits Tau aggregation, suggesting potential relevance to Alzheimer's disease 8. POLDIP2 also regulates mitochondrial morphology and participates in pre-mRNA processing and chromosome 17 9, positioning it as a general regulatory protein in genome stability maintenance.