%0 Journal Article
%T The DNA repair protein DNA-PKcs modulates synaptic plasticity via PSD-95 phosphorylation and stability.
%A Mollinari C
%A Cardinale A
%A Lupacchini L
%A Martire A
%A Chiodi V
%A Martinelli A
%A Rinaldi AM
%A Fini M
%A Pazzaglia S
%A Domenici MR
%A Garaci E
%A Merlo D
%J EMBO Rep
%V 25
%N 8
%D 2024 Aug 31
%M 39085642
%F 9.071
%R 10.1038/s44319-024-00198-3
%X 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.