ArticleNucleic acids research2020
Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair.
Article in Nucleic acids research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 45 citations in OpenAlex.
- Multi-omics analysis in suspected hereditary breast and ovarian cancer cases reveals novel candidate susceptibility factors.NPJ breast cancer · 2026Article
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- H263A and SCAN1/H493R mutant TDP1 block TOP1-induced double-strand break repair during gene transcription in quiescent cells and promote cell death.Cell death & disease · 2025Article
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- Prenatal phenotype of PNKP-related microcephaly, seizures, and developmental delay: A case report and literature review.Medicine · 2025Review
- Plasma pQTL and brain eQTL integration identifies PNKP as a therapeutic target and reveals mechanistic insights into migraine pathophysiology.The journal of headache and pain · 2024Article
- Site-specific acetylation of polynucleotide kinase 3'-phosphatase regulates its distinct role in DNA repair pathways.Nucleic acids research · 2024Article
- Aberrant DNA repair reveals a vulnerability in histone H3.3-mutant brain tumors.Nucleic acids research · 2024Article
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- 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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- The threat of programmed DNA damage to neuronal genome integrity and plasticity.Nature genetics · 2022Review
- Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.EMBO reports · 2021Article
- Article
- DCTPP1, an Oncogene Regulated by miR-378a-3p, Promotes Proliferation of Breast Cancer via DNA Repair Signaling Pathway.Frontiers in oncology · 2021Article
- Mechanisms of Genome Maintenance in Plants: Playing It Safe With Breaks and Bumps.Frontiers in genetics · 2021Review
- Topoisomerase-Mediated DNA Damage in Neurological Disorders.Frontiers in aging neuroscience · 2021Review
- Mutational survivorship bias: The case of PNKP.PloS one · 2020Article
- Linker region is required for efficient nuclear localization of polynucleotide kinase phosphatase.PloS one · 2020Article
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 4 countries.
Funding
Abstract
Hereditary mutations in polynucleotide kinase-phosphatase (PNKP) result in a spectrum of neurological pathologies ranging from neurodevelopmental dysfunction in microcephaly with early onset seizures (MCSZ) to neurodegeneration in ataxia oculomotor apraxia-4 (AOA4) and Charcot-Marie-Tooth disease (CMT2B2). Consistent with this, PNKP is implicated in the repair of both DNA single-strand breaks (SSBs) and DNA double-strand breaks (DSBs); lesions that can trigger neurodegeneration and neurodevelopmental dysfunction, respectively. Surprisingly, however, we did not detect a significant defect in DSB repair (DSBR) in primary fibroblasts from PNKP patients spanning the spectrum of PNKP-mutated pathologies. In contrast, the rate of SSB repair (SSBR) is markedly reduced. Moreover, we show that the restoration of SSBR in patient fibroblasts collectively requires both the DNA kinase and DNA phosphatase activities of PNKP, and the fork-head associated (FHA) domain that interacts with the SSBR protein, XRCC1. Notably, however, the two enzymatic activities of PNKP appear to affect different aspects of disease pathology, with reduced DNA phosphatase activity correlating with neurodevelopmental dysfunction and reduced DNA kinase activity correlating with neurodegeneration. In summary, these data implicate reduced rates of SSBR, not DSBR, as the source of both neurodevelopmental and neurodegenerative pathology in PNKP-mutated disease, and the extent and nature of this reduction as the primary determinant of disease severity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.