A NPAS4-NuA4 complex couples synaptic activity to DNA repair

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 neurons . Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damagi...

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Bibliographic Details
Published in:Nature (London) 2023-02, Vol.614 (7949), p.732-741
Main Authors: 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
Format: Article
Language:English
Subjects:
Aging - genetics
Autism
Basic Helix-Loop-Helix Transcription Factors
Binding sites
Brain
Brain - metabolism
Brain damage
Chromatin
Circuits
Couples
Deoxyribonucleic acid
Disorders
DNA
DNA Breaks, Double-Stranded
DNA damage
DNA Repair
Gene Expression Regulation
Genome
Genomes
Genomic instability
Life span
Longevity - genetics
Lysine Acetyltransferase 5 - metabolism
Mass spectrometry
Multiprotein Complexes - metabolism
Mutation
Neurodegeneration
Neurodegenerative Diseases
Neurodevelopmental disorders
Neurons
Neurons - metabolism
Proteins
Regulatory sequences
Repair
Repair & maintenance
Scientific imaging
Synapses - metabolism
Transcription factors
Transcriptomes
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Summary: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 neurons . 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.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-023-05711-7