Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes
Open accessAbstract
Neuronal activity causes the rapid expression of immediate early genes that are crucial for experience-driven changes to synapses, learning, and memory. Here, using both molecular and genome-wide next-generation sequencing methods, we report that neuronal activity stimulation triggers the formation of DNA double strand breaks (DSBs) in the promoters of a subset of early-response genes, including Fos, Npas4, and Egr1. Generation of targeted DNA DSBs within Fos and Npas4 promoters is sufficient to induce their expression even in the absence of an external stimulus. Activity-dependent DSB formation is likely mediated by the type II topoisomerase, Topoisomerase IIβ (Topo IIβ), and knockdown of Topo IIβ attenuates both DSB formation and early-response gene expression following neuronal stimulation. Our results suggest that DSB formation is a physiological event that rapidly resolves topological constraints to early-response gene expression in neurons.
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Neurons actively induce both DSBs and single-stranded breaks as part of their normal physiology.
“neurons also actively induce both DSBs and single-stranded breaks as part of their normal physiology”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [9]
DSBs play important roles in cell physiology, including T-cell receptor and antibody diversity, chromosomal recombination during meiosis, and immediate early gene expression in neurons.
“DSBs are required for T‐cell receptor and antibody diversity, chromosomal recombination during meiosis, and in the case of neurons, assist in the expression of immediate early genes”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Madabhushi et al, 2015
DNA breaks serve a functional role in neuronal activity.
“DNA breaks seem to serve a functional role in neuronal activity”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Madabhushi et al, 2015
Stimulating primary neurons with bicuculline or subjecting mice to fear learning results in the induction of DSBs at the promoters of immediate-early genes.
“Stimulating primary neurons with bicuculline or subjecting mice to fear learning results in the induction of DSBs at the promoters of immediate‐early genes”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Madabhushi et al, 2015
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- Authors
- Madabhushi, R., Gao, F., Pfenning, A. R., Pan, L., Yamakawa, S., Seo, J., Rueda, R., Phan, T. X., Yamakawa, H., Pao, P.-C., Stott, R. T., Gjoneska, E., Nott, A., Cho, S., Kellis, M., & Tsai, L.-H.
- Affiliations
- Massachusetts Institute of Technology (US)
- Broad Institute (US)
- Corresponding author
- Tsai, Li-Huei
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-06
- Volume
- 161
- Issue
- 7
- Pages
- 1592-1605
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4886855
- OpenAlex
- W2125644182
- Cited by
- 700
- References
- 37
- Citations by year
- 2026: 47 · 2025: 66 · 2024: 67 · 2023: 51 · 2022: 62 · 2021: 66 · 2020: 62 · 2019: 71 · 2018: 74 · 2017: 62 · 2016: 61 · 2015: 11
- FWCI
- 30.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- National Institute on Aging (R01AG046174)
- National Human Genome Research Institute (U01HG007610, RC1HG005334, R01HG004037)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- DNA double-strand breaks, neuronal activity, immediate early genes, FOS, Npas4, EGR1, topoisomerase II beta, topological constraints, gene expression regulation, synaptic plasticity, learning and memory
- MeSH terms
- CCCTC-Binding Factor, Animals, DNA Topoisomerases, Type II, DNA-Binding Proteins, Etoposide, Gene Expression Regulation, Neurons, Repressor Proteins, Genes, fos, Mice, Early Growth Response Protein 1, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, DNA Breaks, Double-Stranded, Genome-Wide Association Study, Transcriptome
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