Bifunctional polynucleotide phosphatase/kinase

PNKP (Bifunctional polynucleotide phosphatase/kinase) is a DNA repair enzyme with dual catalytic activities that removes 3'-phosphates from and phosphorylates 5'-hydroxyl groups on DNA backbone termini (UniProt: Q96T60). It functions as a critical component of both non-homologous end-joining (NHEJ) and base excision repair (BER) pathways, ensuring DNA ends are compatible with extension and ligation during damage repair.

PNKP is expressed broadly and its dysfunction is associated with neurodevelopmental disorders. Biallelic PNKP mutations cause microcephaly, seizures, and developmental delay (MCSZ), characterized by infantile-onset seizures, severe intellectual disability, and progressive microcephaly, as well as ataxia-oculomotor apraxia 4 (AOA4), presenting with cerebellar ataxia and oculomotor apraxia (UniProt: Q96T60).

In Alzheimer's disease, PNKP is significantly down-regulated in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of −0.62 (Chaparral AD proteomics). This reduction in DNA repair capacity may contribute to neuronal vulnerability and neurodegeneration observed in AD pathology.