DNA-directed DNA polymerase alpha catalytic subunit (Pol α) (Pol α)

DNA polymerase alpha (Pol α) is a fundamental enzyme in eukaryotic DNA replication, existing as a heterotetrameric complex with primase. It is uniquely responsible for initiating de novo DNA synthesis by extending an RNA primer with a short segment of nascent DNA, a process essential for both leading and lagging strand synthesis (UniProt: P09884). This enzyme is a primary target for several chemotherapeutic agents, particularly nucleoside analogs like cytarabine and gemcitabine. These drugs exert their effect by competing with natural deoxynucleotides for the active site or by becoming incorporated into the nascent DNA strand, which subsequently causes chain termination (PubMed: 25151158). Inhibition of Pol α leads to the cessation of DNA synthesis, replication stress, and the induction of apoptosis, making it a cornerstone of treatment for various hematological malignancies and solid tumors. Furthermore, the interaction between Pol α and nascent DNA is a focal point for structural studies aimed at developing non-nucleoside inhibitors that can trap the enzyme in a non-functional state (PubMed: 27130968). Beyond cancer, mutations in the POLA1 gene are linked to rare genetic disorders, highlighting its critical role in maintaining genomic integrity and immune signaling (PubMed: 26752517).

Other names

POLA1DNA polymerase alphaDNA polymerase alpha-primase complexp180 subunitDNA-directed DNA polymerase alpha

Inhibition of DNA synthesis through competitive binding with dNTPs at the DNA polymerase alpha active site and/or incorporation into the nascent DNA strand, leading to premature chain termination and replication fork collapse.