PNKP (polynucleotide kinase 3'-phosphatase) is a dual-function DNA repair enzyme essential for maintaining genome stability, particularly in the nervous system. Its primary function involves processing DNA termini through two catalytic activities: removing 3'-phosphates and phosphorylating 5'-hydroxyl groups on the DNA backbone 12. PNKP operates in both base excision repair (BER) and non-homologous end-joining (NHEJ) pathways 3, and additionally protects stalled replication forks from nuclease-dependent degradation during replication stress 4. In transcription, PNKP removes topoisomerase I cleavage complexes, preventing accumulation of transcription-dependent double-strand breaks that could cause neurodegeneration 5. Disease relevance: PNKP mutations cause neurological disorders including ataxia-oculomotor apraxia, microcephaly with seizures, and early-onset neurodegeneration due to impaired DNA repair capacity in neural tissue 6. Beyond inherited disease, PNKP is highly expressed in triple-negative breast cancer and contributes to chemoresistance 7. Recent evidence identifies PNKP as a therapeutic target for migraine, where altered gene expression and protein levels mechanistically influence disease pathogenesis 8. Clinical significance extends to cancer therapy, where PNKP inhibition synergizes with doxorubicin treatment, and to pediatric gliomas where PNKP dysfunction represents a vulnerability in histone H3.3-mutant tumors 9.