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

doi:10.1016/j.cell.2017.06.034

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 journal › Article › peer-review

263 Scopus citations

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.

Original language	English
Pages (from-to)	507-521.e18
Journal	Cell
Volume	170
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2017.06.034
State	Published - 27 Jul 2017
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2017

Funding

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.

Funders	Funder number
Barry Sleckman
Department of Defense Idea Expansion	W81XWH-15-2-006, W81XWH-16-1-0599
Shunichi Takeda
National Institutes of Health	NS-37956
National Cancer Institute	P30CA021765
Ellison Medical Foundation	AG-SS-2633-11
Alex's Lemonade Stand Foundation for Childhood Cancer
St. Jude Children's Research Hospital	UM1HG009375

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2017.06.034

Cite this

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title = "Genome Organization Drives Chromosome Fragility",

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.",

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doi = "10.1016/j.cell.2017.06.034",

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AU - Pekowska, Aleksandra

AU - Zhang, Hongliang

AU - Rao, Suhas S.P.

AU - Huang, Su Chen

AU - Mckinnon, Peter J.

AU - Aplan, Peter D.

AU - Pommier, Yves

AU - Aiden, Erez Lieberman

AU - Casellas, Rafael

AU - Nussenzweig, André

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Genome Organization Drives Chromosome Fragility

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

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