PNKP

PNKP stands for polynucleotide kinase/phosphatase, a dual-function DNA repair enzyme found in humans and many other organisms. It possesses 5'-kinase and 3'-phosphatase activities that process damaged DNA ends to generate ligatable termini. Through these activities, PNKP participates in multiple DNA repair pathways, including base excision repair (BER), single-strand break repair (SSBR) and, via non-homologous end joining (NHEJ), double-strand break repair. By remodeling blocked or abnormal DNA ends, PNKP helps maintain genome integrity after oxidative stress and other insults.

Structurally, PNKP contains an N-terminal forkhead-associated (FHA) domain mediating protein interactions, followed by a catalytic 3'-phosphatase domain and a 5'-kinase domain. The enzyme acts on 3' blocked ends and 5' termini to restore proper ends for ligation. In cells, PNKP is recruited to sites of damage through interactions with scaffold proteins such as XRCC1 in SSBR and XRCC4 in NHEJ, and its activity is linked to PARP signaling.

Mutations in PNKP cause autosomal recessive neurodevelopmental disorders. The best-established syndromes include microcephaly with early-onset seizures (MCSZ) and ataxia-ocular motor apraxia type 4 (AOA4); affected individuals exhibit developmental delay, cerebral atrophy or microcephaly, seizures and coordination problems, with phenotypes ranging in severity. Several pathogenic variants reduce enzymatic activity or disrupt domain function, underscoring the importance of PNKP's end-processing activities for neural development. Heterozygous carriers are typically asymptomatic.

Research on PNKP advances understanding of SSBR and DSB repair coordination. Model organisms and patient-derived cells show that loss of PNKP leads to accumulation of DNA damage in neurons and neurodevelopmental defects, highlighting its role in inherited neurodegenerative disease and DNA repair–related pathologies.