POLD1 encodes the catalytic subunit of DNA polymerase delta, functioning as the primary replicative polymerase for lagging strand synthesis and DNA repair 1. As part of the trimeric (Pol-delta3) or tetrameric (Pol-delta4) complexes with accessory proteins POLD2, POLD3, and POLD4, POLD1 exhibits both polymerase and 3' to 5'-exonuclease (proofreading) activity essential for high-fidelity genome replication 1. POLD1 participates in nucleotide excision repair following UV damage, base-excision repair, and translesion synthesis across damaged DNA templates 2. Germline exonuclease domain variants causing proofreading deficiency are associated with polymerase proofreading-associated syndrome, conferring increased cancer risk (0.1-0.4% of familial cancer cases) 1. These variants predominantly predispose to colorectal, endometrial, and ovarian cancers through ultra-high mutation accumulation 1. Clinically, POLD1 proofreading-deficient colorectal cancers exhibit superior response to immune checkpoint inhibitors (89% overall response rate versus 54% in mismatch repair-deficient tumors) and improved survival outcomes, making POLD1/POLE mutation status a valuable biomarker for immunotherapy selection 3. Current guidelines recommend POLD1 gene mutation testing for colorectal cancer patients 4. POLD1 loss is also implicated in chemotherapy resistance in triple-negative breast cancer 5.