POLA2 encodes the accessory subunit of DNA polymerase alpha complex, which plays an essential role in DNA replication initiation during S phase 1. The polymerase alpha complex initiates DNA synthesis by oligomerizing short RNA primers on both leading and lagging strands, with primers initially extended by the polymerase alpha catalytic subunit before transfer to delta and epsilon polymerases 1. Beyond replication initiation, POLA2 functions in DNA double-strand break (DSB) repair through both non-homologous end-joining and homologous recombination pathways 2. Loss of POLA2 increases spontaneous DSB formation, slows repair kinetics, and increases sensitivity to ionizing radiation and PARP1 inhibition 2. POLA2 is also crucial for telomere C-strand fill-in, with biallelic variants causing autosomal recessive telomere biology disorders with Coats plus features 3. Clinically, POLA2 variants are associated with early-onset colorectal cancer susceptibility 4, and a specific SNP (G583R) affects protein nuclear localization and correlates with improved survival in non-small cell lung cancer patients receiving gemcitabine therapy 5. POLA2 expression is elevated in hepatocellular carcinoma and glioblastoma, correlating with poor patient survival 6.