DNA polymerase alpha (POLA1) and DNA polymerase epsilon (POLE) (DNA Pol alpha/epsilon)

DNA polymerase alpha and DNA polymerase epsilon are essential enzymes in the eukaryotic DNA replication machinery, responsible for synthesizing the lagging and leading strands, respectively [1, 2]. These enzymes are the primary therapeutic targets of clofarabine, a second-generation purine nucleoside analog used in the treatment of pediatric and adult leukemias [3, 7]. Clofarabine is converted into an active triphosphate form that competes with natural nucleotides for binding to these polymerases and is subsequently incorporated into the growing DNA chain [5, 8]. This incorporation causes premature chain termination and replication fork arrest, which triggers DNA damage signaling and programmed cell death [4, 10]. Because malignant cells in leukemia exhibit high rates of DNA replication, they are particularly sensitive to the inhibition of these polymerases [11, 12]. The therapeutic efficacy of targeting these enzymes is often enhanced by the simultaneous inhibition of ribonucleotide reductase, which depletes the competing natural nucleotide pools [6, 9].

Other names

DNA-directed DNA polymerasePOLA1POLEReplicative DNA polymeraseDNA polymerase alpha catalytic subunitDNA polymerase epsilon catalytic subunit

Clofarabine is phosphorylated to its active triphosphate form, which inhibits DNA synthesis by competing with dATP for incorporation into DNA by DNA polymerase alpha and epsilon [1, 3]. Once incorporated into the nascent DNA strand, it acts as a chain terminator, leading to replication fork arrest, DNA strand breaks, and the induction of apoptosis [5, 8].