Genome Organization Drives Chromosome Fragility
Open accessAbstract
In this study, we show that evolutionarily conserved chromosome loop anchors bound by CCCTC-binding factor (CTCF) and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy rewire DNA cleavage sites to novel loop anchors. While transcription- and replication-coupled genomic rearrangements have been well documented, we demonstrate that DSBs formed at loop anchors are largely transcription-, replication-, and cell-type-independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in cancer. Thus, loop anchors serve as fragile sites that generate DSBs and chromosomal rearrangements. VIDEO ABSTRACT.
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Loop boundaries are hotspots for TOP2B-mediated DNA breaks in T-cells and B-cells.
“loop boundaries are hotspots for TOP2 B-mediated DNA breaks in T-cells and B-cells”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [28]
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- Authors
- Canela, A., Maman, Y., Jung, S., Wong, N., Callen, E., Day, A., Kieffer-Kwon, K.-R., Pekowska, A., Zhang, H., Rao, S. S. P., Huang, S.-C., Mckinnon, P. J., Aplan, P. D., Pommier, Y., Aiden, E. L., Casellas, R., & Nussenzweig, A.
- Affiliations
- National Institutes of Health (US)
- Baylor College of Medicine (US)
- St. Jude Children's Research Hospital (US)
- National Cancer Institute (US)
- Corresponding author
- Nussenzweig, André
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 170
- Issue
- 3
- Pages
- 507-521.e18
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6133249
- OpenAlex
- W2737563286
- Cited by
- 383
- References
- 70
- Citations by year
- 2026: 19 · 2025: 30 · 2024: 36 · 2023: 40 · 2022: 39 · 2021: 47 · 2020: 57 · 2019: 52 · 2018: 51 · 2017: 10 · 2016: 1
- FWCI
- 19.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- UWA Profiles and Research Repository (UWA) (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Intramural Research Program of the NIH
- NIH (NS-37956, CA-21765)
- CCSG (P30 CA21765)
- St. Jude Children’s Research Hospital
- NIH Encyclopedia of DNA Elements Mapping Center Award (UM1HG009375)
- President’s Early Career Award in Science and Engineering
- Ellison Medical Foundation Senior Scholar (AG-SS-2633-11)
- Department of Defense Idea Expansion (W81XWH-15-2-006)
- Breakthrough (W81XWH-16-1-0599)
- Alex Lemonade Stand Foundation
- 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 › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- chromosome fragility, fragile sites, DNA double-strand breaks, CTCF, cohesin, topological domains, genome organization, chromosomal rearrangements, interphase
- MeSH terms
- Poly-ADP-Ribose Binding Proteins, CCCTC-Binding Factor, Animals, B-Lymphocytes, Chromosome Fragility, DNA Topoisomerases, Type II, DNA-Binding Proteins, Humans, Mice, Inbred C57BL, Neoplasms, Repressor Proteins, Cell Line, Tumor, Mice, DNA Breaks, Double-Stranded
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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