PDF(Pubmed)
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.
摘要：
关键的DNA修复酶DNA-PKcs具有几个重要的细胞功能。小鼠DNA-PKcs活性的丧失揭示了在免疫和神经系统中的重要作用。在人类中,DNA-PKcs是大脑发育和功能的关键因素，因为prkdc基因的突变会导致严重的神经功能缺损，如小头畸形和癫痫发作。预测DNA-PKcs在神经元中的未知作用。在这里，我们表明DNA-PKcs调节突触可塑性。我们证明DNA-PKcs定位于突触并在新鉴定的控制PSD-95蛋白稳定性的残基处磷酸化PSD-95。DNA-PKcs-/-小鼠的特征是长期增强（LTP）受损，神经元形态的变化，和降低突触后蛋白的水平。当在DNA-PKcs-/-小鼠中过表达时,组成型磷酸化的PSD-95突变体挽救LTP损伤。我们的研究确定了DNA-PKcs在调节神经元可塑性方面的新兴生理功能，超越基因组稳定性。
