DNA polymerase alpha catalytic subunit (POLA1) (POLA1)

DNA polymerase alpha catalytic subunit (POLA1) is a fundamental enzyme responsible for the initiation of DNA replication in eukaryotic cells. As the largest subunit of the four-protein DNA polymerase alpha-primase complex, it extends the short RNA primers synthesized by the primase subunits with approximately 20 deoxynucleotides, creating the RNA-DNA chimeric primers required for the processive polymerases delta and epsilon to take over. Beyond its nuclear role in the S phase of the cell cycle, POLA1 also functions in the cytosol to maintain a physiological concentration of RNA:DNA hybrids, which serve as critical negative regulators of the cGAS-STING pathway to prevent the spontaneous activation of type I interferon responses. Mutations in the POLA1 gene are associated with rare X-linked disorders such as reticulate pigmentary disorder (XLPDR) and Van Esch-O'Driscoll syndrome (VEODS), which manifest as immunodeficiency, growth retardation, and autoinflammation. In the context of oncology, POLA1 is frequently overexpressed in various malignancies, including colorectal and bladder cancers, making it a viable therapeutic target for small-molecule inhibitors like CD437 and ST1926 that induce replication stress and apoptosis in rapidly proliferating cells.

Other names

DNA polymerase alpha 1p180POLANSXPDRVEODSPolymerase (DNA directed), alpha 1

Inhibition of the catalytic active site to prevent DNA template and nucleotide binding, leading to the disruption of RNA-DNA primer synthesis, induction of replication stress, and triggering of apoptosis.