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Long Neural Genes Harbor Recurrent DNA Break Clusters in Neural Stem/Progenitor Cells
Open accessAbstract
Repair of DNA double-strand breaks (DSBs) by non-homologous end joining is critical for neural development, and brain cells frequently contain somatic genomic variations that might involve DSB intermediates. We now use an unbiased, high-throughput approach to identify genomic regions harboring recurrent DSBs in primary neural stem/progenitor cells (NSPCs). We identify 27 recurrent DSB clusters (RDCs), and remarkably, all occur within gene bodies. Most of these NSPC RDCs were detected only upon mild, aphidicolin-induced replication stress, providing a nucleotide-resolution view of replication-associated genomic fragile sites. The vast majority of RDCs occur in long, transcribed, and late-replicating genes. Moreover, almost 90% of identified RDC-containing genes are involved in synapse function and/or neural cell adhesion, with a substantial fraction also implicated in tumor suppression and/or mental disorders. Our characterization of NSPC RDCs reveals a basis of gene fragility and suggests potential impacts of DNA breaks on neurodevelopment and neural functions.
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“Indeed, we find that long-neural genes with synaptic and cell adhesion genes associated with the recurrent DNA double-strand breaks and AD GWAS genes are enriched for gene fusions 73.”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [73]
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“we are just beginning to appreciate the significance of a lesion’s genomic location in relation to its effect on neuronal activity and, ultimately, degeneration”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Wei et al, 2016
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Metadata
- Authors
- Wei, P.-C., Chang, A. N., Kao, J., Du, Z., Meyers, R. M., Alt, F. W., & Schwer, B.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- Alt, Frederick W.
- Schwer, Bjoern
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 164
- Issue
- 4
- Pages
- 644-655
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4752721
- OpenAlex
- W2268858163
- Cited by
- 280
- References
- 55
- Citations by year
- 2026: 20 · 2025: 13 · 2024: 15 · 2023: 23 · 2022: 24 · 2021: 32 · 2020: 31 · 2019: 20 · 2018: 37 · 2017: 40 · 2016: 25
- FWCI
- 21.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 376 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute on Aging (K01AG043630)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- neural stem/progenitor cells, DNA double-strand breaks, non-homologous end joining, replication stress, synaptic function, neuronal adhesion, tumor suppression genes, mental illness, brain development
- MeSH terms
- Animals, Brain, Cell Adhesion, DNA Repair, Humans, Nerve Tissue Proteins, Synapses, Transcription Factors, Translocation, Genetic, Cell Adhesion Molecules, Neuronal, Aphidicolin, Genome, Mice, Basic Helix-Loop-Helix Proteins, DNA Breaks, GPI-Linked Proteins, Neural Stem Cells, DNA End-Joining Repair
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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