NPAS4–NuA4 复合物将突触活动与 DNA 修复结合起来。相关的大脑活动会引发大量DNA的断裂，进而损伤神经元。
生物探索
2023/02/23
论文
论文标题：A NPAS4–NuA4 complex couples synaptic activity to DNA repair
作者：Pollina, Elizabeth A., Gilliam, Daniel T., Landau, Andrew T., Lin, Cindy, Pajarillo, Naomi, Davis, Christopher P., Harmin, David A., Yap, Ee-Lynn, Vogel, Ian R., Griffith, Eric C., Nagy, M. Aurel, Ling, Emi, Duffy, Erin E., Sabatini, Bernardo L., Weitz, Charles J., Greenberg, Michael E.
期刊：Nature
发表时间：2023/02/15
数字识别码：10.1038/s41586-023-05711-7
摘要：Neuronal activity is crucial for adaptive circuit remodelling but poses an inherent risk to the stability of the genome across the long lifespan of postmitotic neurons1,2,3,4,5. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is unknown. Here we identify an activity-dependent DNA repair mechanism in which a new form of the NuA4–TIP60 chromatin modifier assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex from the brain and demonstrate its functions in eliciting activity-dependent changes to neuronal transcriptomes and circuitry. By characterizing the landscape of activity-induced DNA double-strand breaks in the brain, we show that NPAS4–NuA4 binds to recurrently damaged regulatory elements and recruits additional DNA repair machinery to stimulate their repair. Gene regulatory elements bound by NPAS4–NuA4 are partially protected against age-dependent accumulation of somatic mutations. Impaired NPAS4–NuA4 signalling leads to a cascade of cellular defects, including dysregulated activity-dependent transcriptional responses, loss of control over neuronal inhibition and genome instability, which all culminate to reduce organismal lifespan. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental and autism spectrum disorders. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation, the disruption of which may contribute to developmental disorders, neurodegeneration and ageing.
近日，来自哈佛医学院的研究人员在Nature上发表了一篇题为“A NPAS4-NuA4 complex couples synaptic activity to DNA repair”的研究论文。该项研究发现了神经元中存在着一种独特的DNA修复机制，解释了为什么神经元在高强度重复工作的情况下仍然能够持续发挥作用。
[1]Pollina EA, Gilliam DT, Landau AT, et al. A NPAS4-NuA4 complex couples synaptic activity to DNA repair. Nature. 2023 Feb 15. doi: 10.1038/s41586-023-05711-7. Epub ahead of print. PMID: 36792830.
