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

DNA-directed DNA polymerase alpha (Pol alpha) is a fundamental enzyme complex required for the initiation of DNA replication in eukaryotic cells (UniProt, P09884). It is composed of four subunits, including the catalytic subunit POLA1 and a primase complex, which work in tandem to synthesize short RNA-DNA primers on both the leading and lagging strands (PubMed, PMC3519554). This activity is a prerequisite for the subsequent action of more processive polymerases like Pol delta and Pol epsilon. Due to its central role in the cell cycle, Pol alpha is a major therapeutic target for antimetabolite drugs used in oncology (StatPearls, NBK526072). Fludarabine, specifically in its active form F-ara-ATP, acts as a potent inhibitor of Pol alpha by competing with natural dNTPs and incorporating into the DNA chain (PubChem, CID 30751). This incorporation causes DNA strand termination and stalls replication forks, ultimately triggering programmed cell death in rapidly dividing cells (NIH, DrugRecord). Consequently, Pol alpha inhibition is a cornerstone in the treatment of various hematologic malignancies, including chronic lymphocytic leukemia (PubMed, 15023711).

Other names

DNA-directed DNA polymerase alpha catalytic subunitPOLA1DNA polymerase alpha complexP70/P180 complexDNA polymerase alpha

Fludarabine (as F-ara-ATP) acts as a competitive inhibitor of DNA polymerase alpha against dATP and incorporates into the growing DNA strand, leading to chain termination and inhibition of further elongation (StatPearls, NBK526072; PubChem, CID 30751).