ArticleScientific reports2022
Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor.
Article in Scientific reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 14 citations in OpenAlex.
- Microcephaly, seizures and developmental delay caused by two novel mutations in theTranslational pediatrics · 2026Article
- Fructose-2,6-bisphosphate restores TDP-43 pathology-driven genome repair deficiency in motor neuron diseases.Communications biology · 2026Article
- F2,6BP restores mitochondrial genome integrity in Huntington's disease.The Journal of biological chemistry · 2026Article
- Compound HeterozygousNeuroSci · 2025Article
- Prenatal phenotype of PNKP-related microcephaly, seizures, and developmental delay: A case report and literature review.Medicine · 2025Review
- CDK-dependent phosphorylation regulates PNKP function in DNA replication.The Journal of biological chemistry · 2024Article
- RFX2 promotes tumor cell stemness through epigenetic regulation of PAF1 in spinal ependymoma.Journal of neuro-oncology · 2023Article
- Zika Virus Induces Mitotic Catastrophe in Human Neural Progenitors by Triggering Unscheduled Mitotic Entry in the Presence of DNA Damage While Functionally Depleting Nuclear PNKP.Journal of virology · 2022Article
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Authors and funding
16 authors at 6 institutions in 2 countries.
Funding
Abstract
Polynucleotide Kinase-Phosphatase (PNKP) is a bifunctional enzyme that possesses both DNA 3'-phosphatase and DNA 5'-kinase activities, which are required for processing termini of single- and double-strand breaks generated by reactive oxygen species (ROS), ionizing radiation and topoisomerase I poisons. Even though PNKP is central to DNA repair, there have been no reports linking PNKP mutations in a Microcephaly, Seizures, and Developmental Delay (MSCZ) patient to cancer. Here, we characterized the biochemical significance of 2 germ-line point mutations in the PNKP gene of a 3-year old male with MSCZ who presented with a high-grade brain tumor (glioblastoma multiforme) within the cerebellum. Functional and biochemical studies demonstrated these PNKP mutations significantly diminished DNA kinase/phosphatase activities, altered its cellular distribution, caused defective repair of DNA single/double stranded breaks, and were associated with a higher propensity for oncogenic transformation. Our findings indicate that specific PNKP mutations may contribute to tumor initiation within susceptible cells in the CNS by limiting DNA damage repair and increasing rates of spontaneous mutations resulting in pediatric glioma associated driver mutations such as ATRX and TP53.
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Registered trials
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