POLD3 serves as an accessory subunit of both DNA polymerase delta (Pol-δ) and DNA polymerase zeta (Pol-ζ) complexes, playing critical roles in genome stability and DNA repair 1. As a component of Pol-δ, POLD3 is essential for high-fidelity DNA replication, particularly lagging strand synthesis, and optimal polymerase activity 1. The protein stabilizes polymerase complexes and facilitates PCNA-mediated stimulation 1. POLD3 exhibits distinct functional properties depending on complex composition - Pol-δ3 (without POLD4) shows higher proofreading activity and reduced strand displacement compared to Pol-δ4, making it better suited for Okazaki fragment processing 1. In DNA repair contexts, POLD3 participates in nucleotide excision repair synthesis, break-induced replication under replication stress, and translesion synthesis across DNA lesions 1. The protein also functions in transcription-coupled double-strand break repair, working with BLM helicase to handle RNA-DNA hybrid accumulation and promote homologous recombination 2. Additionally, POLD3 contributes to chr11 through FA pathway-mediated mitotic DNA synthesis 3. Clinically, POLD3 deficiency causes severe combined immunodeficiency with neurodevelopmental delay and hearing impairment 4, while genetic variants are associated with increased colorectal cancer risk 56.