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The DNA repair protein DNA-PKcs modulates synaptic plasticity via PSD-95 phosphorylation and stability

TitleThe DNA repair protein DNA-PKcs modulates synaptic plasticity via PSD-95 phosphorylation and stability
Publication TypeArticolo su Rivista peer-reviewed
Year of Publication2024
AuthorsMollinari, Cristiana, Cardinale Alessio, Lupacchini Leonardo, Martire Alberto, Chiodi Valentina, Martinelli Andrea, Rinaldi Anna Maria, Fini Massimo, Pazzaglia Simonetta, Domenici Maria Rosaria, Garaci Enrico, and Merlo Daniela
JournalEMBO Reports
Volume25
Pagination3707 – 3737
Type of ArticleArticle
ISSN1469221X
Abstract

The key DNA repair enzyme DNA-PKcs has several and important cellular functions. Loss of DNA-PKcs activity in mice has revealed essential roles in immune and nervous systems. In humans, DNA-PKcs is a critical factor for brain development and function since mutation of the prkdc gene causes severe neurological deficits such as microcephaly and seizures, predicting yet unknown roles of DNA-PKcs in neurons. Here we show that DNA-PKcs modulates synaptic plasticity. We demonstrate that DNA-PKcs localizes at synapses and phosphorylates PSD-95 at newly identified residues controlling PSD-95 protein stability. DNA-PKcs −/− mice are characterized by impaired Long-Term Potentiation (LTP), changes in neuronal morphology, and reduced levels of postsynaptic proteins. A PSD-95 mutant that is constitutively phosphorylated rescues LTP impairment when over-expressed in DNA-PKcs −/− mice. Our study identifies an emergent physiological function of DNA-PKcs in regulating neuronal plasticity, beyond genome stability. © The Author(s) 2024.

Notes

Cited by: 0; All Open Access, Green Open Access

URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85200893975&doi=10.1038%2fs44319-024-00198-3&partnerID=40&md5=cea8a9b6d79aafb80565380fb4e43052
DOI10.1038/s44319-024-00198-3
Citation KeyMollinari20243707
PubMed ID39085642