POLE4 is an accessory subunit of DNA polymerase epsilon (Polε), the major leading strand polymerase in eukaryotes 1. POLE4 functions within the Polε complex to regulate multiple aspects of DNA metabolism: it facilitates leading strand synthesis through control of PCNA processivity and DNA grip mechanisms 2, acts as a histone H3-H4 chaperone to maintain chr2 integrity during replication 3, and participates in asymmetric H3K9me3 distribution to silence LINE retrotransposons in S phase 4. POLE4 loss destabilizes the entire Polε complex, causing replication stress and p53 activation 1. Clinically, POLE4 deficiency sensitizes cancer cells to PARP inhibitors through accumulation of replication gaps and impaired post-replicative repair, independent of homologous recombination status 56. This sensitivity operates parallel to BRCA1-mediated pathways and can overcome acquired PARPi resistance, positioning POLE4 as a therapeutic target 5. POLE4 also requires iron-sulfur cluster-dependent cofactors for optimal Polε function 2, and its expression levels correlate with survival outcomes in melanoma 7. The protein's role extends to facilitating DNA repair in radiation-injured tissues 8.