PXD038718-1

PXD038718 is an original dataset announced via ProteomeXchange.

Title	An NPAS4:NuA4 complex couples synaptic activity to DNA repair
Description	Neuronal 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.
HostingRepository	PRIDE
AnnounceDate	2023-02-15
AnnouncementXML	Submission_2023-02-15_11:48:50.729.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	DanielGilliam
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-09 05:27:42	ID requested
⏵ 1	2023-02-15 11:48:51	announced
2	2023-02-27 06:46:19	announced	2023-02-27: Updated project metadata.
3	2023-11-14 07:19:30	announced	2023-11-14: Updated project metadata.
4	2023-11-14 08:59:23	announced	2023-11-14: Updated project metadata.

submitter keyword: NuA4, Mus musculus, Hippocampus, Tip60, HEK293T,Npas4

MichaelGreenberg
contact affiliation	Harvard Medical School Department of Neurobiology
contact email	Michael_Greenberg@hms.harvard.edu
lab head
DanielGilliam
contact affiliation	Harvard Medical School
contact email	danielgilliam10@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD038718
     1. Label: PRIDE project
     2. Name: An NPAS4:NuA4 complex couples synaptic activity to DNA repair