Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
30 03 2022
30 03 2022
Historique:
received:
10
10
2021
accepted:
04
03
2022
entrez:
31
3
2022
pubmed:
1
4
2022
medline:
2
4
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35354845
doi: 10.1038/s41598-022-09097-w
pii: 10.1038/s41598-022-09097-w
pmc: PMC8967877
doi:
Substances chimiques
PNKP protein, human
EC 2.7.1.-
Phosphotransferases (Alcohol Group Acceptor)
EC 2.7.1.-
DNA Repair Enzymes
EC 6.5.1.-
Types de publication
Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5386Subventions
Organisme : NCI NIH HHS
ID : P50 CA211015
Pays : United States
Organisme : NINDS NIH HHS
ID : R25NS079200
Pays : United States
Informations de copyright
© 2022. The Author(s).
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