Genome Organization Drives Chromosome Fragility

Andres Canela, Yaakov Maman, Seolkyoung Jung, Nancy Wong, Elsa Callen, Amanda Day, Kyong Rim Kieffer-Kwon, Aleksandra Pekowska, Hongliang Zhang, Suhas S.P. Rao, Su Chen Huang, Peter J. Mckinnon, Peter D. Aplan, Yves Pommier, Erez Lieberman Aiden, Rafael Casellas, André Nussenzweig

Research output: Contribution to journalArticlepeer-review

132 Scopus citations


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.

Original languageEnglish
Pages (from-to)507-521.e18
Issue number3
StatePublished - 27 Jul 2017
Externally publishedYes

Bibliographical note

Funding Information:
We thank Barry Sleckman, Shunichi Takeda, and Noritaka Adachi for cell lines and Xuguang Tai for assistance on T cells, Sam John, John Crispino, John Nitiss, and James Berger for stimulating discussions, and sequencing support from David Goldstein and the CCR Genomics Core. The A.N., P.D.A, Y.P., and R.C. laboratories are supported by the Intramural Research Program of the NIH. P.J.M. is supported by the NIH (NS-37956 and CA-21765), the CCSG (P30 CA21765), and St. Jude Children's Research Hospital. E.L.A. is supported by an NIH Encyclopedia of DNA Elements Mapping Center Award (UM1HG009375) and the President's Early Career Award in Science and Engineering. A.N. is supported by an Ellison Medical Foundation Senior Scholar in Aging Award (AG-SS-2633-11), the Department of Defense Idea Expansion (W81XWH-15-2-006) and Breakthrough (W81XWH-16-1-0599) Awards, and an Alex Lemonade Stand Foundation Award.

Publisher Copyright:
© 2017


  • DNA breaks
  • breakpoint cluster regions
  • cancer
  • fragile sites
  • genome instability
  • topoisomerase
  • topologically associated domains
  • translocations


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