POLA1 encodes the catalytic subunit of DNA polymerase alpha, an essential enzyme complex that initiates DNA replication during the S phase of the cell cycle 1. The polymerase alpha complex, composed of POLA1, POLA2, and two primase subunits, is recruited to replicative forks where it synthesizes short RNA primers and extends them with limited processivity before transferring to more processive polymerases 1. Beyond replication, POLA1 contributes to maintaining cytosolic RNA:DNA hybrids that prevent spontaneous type I interferon activation 1. Pathogenic mutations in POLA1 cause two distinct X-linked disorders: X-linked reticulate pigmentary disorder (XLPDR), characterized by skin hyperpigmentation, inflammation, and immune dysfunction including NK cell defects, and van Esch-O'Driscoll syndrome (VEODS), featuring growth retardation and microcephaly 1. POLA1 variants have also been identified in dyskeratosis congenita, affecting telomere biology 2. Clinically, POLA1 represents a promising therapeutic target in cancer treatment. Synthetic lethality exists between ATR/CHK1 pathway defects and POLA1 inhibition, suggesting potential for individualized cancer therapy 3. High POLA1 expression levels may predict resistance to CHK1 inhibitors in ovarian cancer, while dual POLA1-HDAC inhibitors show antitumor activity 45.