PNKP (polynucleotide kinase 3'-phosphatase) is a bifunctional DNA repair enzyme essential for maintaining genome stability. Through its dual catalytic activities—5'-kinase and 3'-phosphatase—PNKP prepares DNA termini for extension and ligation by phosphorylating 5'-hydroxyl groups or removing 3'-phosphates from damaged DNA 1. The protein functions in both base excision repair (BER) and non-homologous end joining (NHEJ) pathways, and also protects stalled replication forks from nucleolytic degradation during replication stress 2. Pathogenic variants in PNKP cause severe neurodevelopmental and neurodegenerative disorders, including ataxia with oculomotor apraxia type 4 and microcephaly with seizures and developmental delay, reflecting the nervous system's particular dependence on genomic stability 3. Deficiency in PNKP function impairs the resolution of transcription-associated DNA damage, promoting neurodegeneration 4. At the population level, gnomAD v4.1 classifies this gene as LoF-tolerant (LOEUF=1.53) because heterozygous carriers are viable; this is distinct from clinical pathogenicity in disease contexts, where 143 ClinVar pathogenic variants have been identified. Recent studies identify PNKP as a therapeutic target in cancer contexts. In triple-negative breast cancer, PNKP targeting enhances ferroptosis and synergizes with doxorubicin 5. In histone H3.3-mutant pediatric gliomas, PNKP inhibition presents a therapeutic vulnerability specific to mutant cells 6. Genome-wide association integration identifies PNKP as a migraine therapeutic target through mechanisms involving glutamate metabolism 7.