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

252 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 (US)
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 - Jul 27 2017
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2017.06.034

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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.",

keywords = "breakpoint cluster regions, cancer, DNA breaks, fragile sites, genome instability, topoisomerase, topologically associated domains, translocations",

author = "Andres Canela and Yaakov Maman and Seolkyoung Jung and Nancy Wong and Elsa Callen and Amanda Day and Kieffer-Kwon, {Kyong Rim} and Aleksandra Pekowska and Hongliang Zhang and Rao, {Suhas S.P.} and Huang, {Su Chen} and Mckinnon, {Peter J.} and Aplan, {Peter D.} and Yves Pommier and Aiden, {Erez Lieberman} and Rafael Casellas and Andr{\'e} Nussenzweig",

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month = jul,

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

language = "English (US)",

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T1 - Genome Organization Drives Chromosome Fragility

AU - Canela, Andres

AU - Maman, Yaakov

AU - Jung, Seolkyoung

AU - Wong, Nancy

AU - Callen, Elsa

AU - Day, Amanda

AU - Kieffer-Kwon, Kyong Rim

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

PY - 2017/7/27

Y1 - 2017/7/27

N2 - 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.

AB - 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.

KW - breakpoint cluster regions

KW - cancer

KW - DNA breaks

KW - fragile sites

KW - genome instability

KW - topoisomerase

KW - topologically associated domains

KW - translocations

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VL - 170

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JO - Cell

JF - Cell

IS - 3

ER -

Genome Organization Drives Chromosome Fragility

Abstract

Keywords

ASJC Scopus subject areas

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