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PXD038718 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleAn NPAS4:NuA4 complex couples synaptic activity to DNA repair
DescriptionNeuronal activity is critical for adaptive circuit remodeling but poses an inherent risk to the stability of the genome across the long lifespan of post-mitotic neurons1-5. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is not known. Here we identify an activity-dependent DNA repair mechanism via a new form of the NuA4/TIP60 chromatin modifier that assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex directly from the brain and demonstrate its functions in eliciting activity-dependent changes to neuronal transcriptomes and circuitry. By identifying the landscape of activity-induced DNA double-strand breaks in the brain, we show that the NPAS4:NuA4 complex binds to recurrently damaged regulatory elements and recruits additional DNA repair machinery to stimulate their repair. Gene regulatory elements bound by the NPAS4:NuA4 complex are partially protected from age-dependent accumulation of somatic mutations. Impaired NPAS4:NuA4 signaling leads to a cascade of cellular defects including dysregulated transcriptional responses to activity, loss of control over neuronal inhibition, and genome instability, culminating in reduced organismal lifespan. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental disorders and autism. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation and whose disruption may contribute to developmental disorders, neurodegeneration and aging.
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListNo PTMs are included in the dataset
InstrumentLTQ Orbitrap Velos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-12-09 05:27:42ID requested
12023-02-15 11:48:51announced
22023-02-27 06:46:19announced2023-02-27: Updated project metadata.
Publication List
Pollina EA, Gilliam DT, Landau AT, Lin C, Pajarillo N, Davis CP, Harmin DA, Yap EL, Vogel IR, Griffith EC, Nagy MA, Ling E, Duffy EE, Sabatini BL, Weitz CJ, Greenberg ME, A NPAS4-NuA4 complex couples synaptic activity to DNA repair. Nature, 614(7949):732-741(2023) [pubmed]
Keyword List
submitter keyword: NuA4, Mus musculus, Hippocampus, Tip60, HEK293T,Npas4
Contact List
contact affiliationHarvard Medical School Department of Neurobiology
contact emailMichael_Greenberg@hms.harvard.edu
lab head
contact affiliationHarvard Medical School
contact emaildanielgilliam10@gmail.com
dataset submitter
Full Dataset Link List
Dataset FTP location
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PRIDE project URI
Repository Record List
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