Omics · study · 2026
TDP2-mediated DNA repair regulates the dynamics of neuronal early response gene transcription and cortical neuron connectivity
Listed in NCBI GEO
Neuronal activity induces topoisomerase IIb (TOP2B) to form DNA double strand breaks (DSBs) within the promoters of specific early response genes (ERGs), such as Fos, FosB, and Npas4, and these DSBs facilitate rapid ERG transcription.
Description
Yet how activity-induced DSBs are repaired and the significance of such mechanisms for neuronal function remain unclear. Here we show that the proteasome and the enzyme, tyrosyl-DNA phosphodiesterase 2 (TDP2), catalyze the initial processing of TOP2B-mediated DSBs in neurons.
Knockdown of Tdp2 delayed the repair of neuronal activity-induced DSBs and prolonged the expression of ERGs in primary mouse cortical neurons, indicating that TDP2-mediated DNA repair is essential for the temporal control of ERG transcription. Deletion of Tdp2 in excitatory forebrain neurons caused DSB accrual and ERG overexpression, and these changes were associated with increased excitatory synaptic transmission and cortical circuit dysfunction.
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Mutations in TDP2 cause the disease, SCAR23 (spinocerebellar ataxia, autosomal recessive 23), which manifests predominantly with neurological abnormalities. We show that whereas proliferating cells possess redundant pathways to process TOP2B-mediated DSBs, these pathways are relatively inactive in postmitotic neurons. Together, these results underscore the neuroprotective roles of TDP2 and suggest that activity-induced DSBs could be relevant sources of DNA lesions for neurodegeneration.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE305nnn/GSE305228 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE305228 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1304873 ncbi.nlm.nih.gov/bioproject/PRJNA1304873 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Mus musculus
- From keywords
- Life Sciences
- Inferred from text
- Disease 75%
Provenance · 1 source records, 8 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE305228 | 15 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[organism].NCBITaxon:10090 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |