PRIMPOL is a dual-function enzyme possessing both primase and DNA polymerase activities essential for tolerating replication-stalling lesions in nuclear and mitochondrial DNA 1. Its primary function involves reinitiating DNA synthesis downstream of DNA lesions—including UV lesions, abasic sites, 8-oxoguanine, and G-quadruplexes—through de novo primer synthesis, allowing replication fork progression to bypass damage 234. PRIMPOL operates as an error-prone polymerase capable of directly synthesizing across certain lesions or repriming ahead of unreadable damage, thereby skipping lesions while leaving ssDNA gaps for post-replicative repair 56. Mechanistically, PRIMPOL uses its N-terminal catalytic domain and C-terminal zinc-finger motif cooperatively to initiate DNA synthesis in cis-orientation 7. The enzyme's repriming activity is regulated by ATR-dependent phosphorylation at Ser255 and associates with MCM10 to modulate fork progression during DNA damage responses 89. PRIMPOL-generated ssDNA gaps are subsequently filled through temporally distinct pathways involving REV1-POLζ translesion synthesis in G2 phase or RAD51-mediated recombination in S phase 6. Clinically, PRIMPOL dysfunction is associated with autosomal dominant myopia 22 10, while PRIMPOL pathway inhibition represents a novel therapeutic strategy to enhance chemosensitivity in cancer cells 51.