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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
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