Cited by 383Genomics and Chromatin DynamicsDNA Repair MechanismsGenomic variations and chromosomal abnormalities

Genome Organization Drives Chromosome Fragility

Open access
Canela, Andres, Maman, Yaakov, Jung, Seolkyoung, Wong, Nancy, Callen, Elsa, Day, Amanda, Kieffer-Kwon, Kyong-Rim, Pekowska, Aleksandra +9 more·2017·Cell

Abstract

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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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
Venue
Cell
Publisher
Elsevier BV
Published
2017-07
Volume
170
Issue
3
Pages
507-521.e18
ISSN
0092-8674 (ISSN-L)
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
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

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