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

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. Synopsis: DNA-PKcs has a role in neuronal plasticity via PSD-95 phosphorylation and regulation of its protein stability, revealing a physiological role beyond its function in DNA repair. Synaptic DNA-PKcs phosphorylates PSD-95 at newly identified residues. DNA-PKcs phopshorylation controls PSD-95 protein stability. Lack of DNA-PKcs affects synaptic plasticity. Constitutively phosphorylated PSD-95 rescues LTP impairment when over-expressed in DNA-PKcs −/− mice. DNA-PKcs has a role in neuronal plasticity via PSD-95 phosphorylation and regulation of its protein stability, revealing a physiological role beyond its function in DNA repair. [ABSTRACT FROM AUTHOR]