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

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

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

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

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

Access to Document

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.",

keywords = "DNA breaks, breakpoint cluster regions, cancer, 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",

note = "Publisher Copyright: {\textcopyright} 2017",

year = "2017",

month = jul,

day = "27",

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

language = "الإنجليزيّة",

volume = "170",

pages = "507--521.e18",

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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 - DNA breaks

KW - breakpoint cluster regions

KW - cancer

KW - fragile sites

KW - genome instability

KW - topoisomerase

KW - topologically associated domains

KW - translocations

UR - http://www.scopus.com/inward/record.url?scp=85026385108&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2017.06.034

DO - 10.1016/j.cell.2017.06.034

M3 - مقالة

C2 - 28735753

SN - 0092-8674

VL - 170

SP - 507-521.e18

JO - Cell

JF - Cell

IS - 3

ER -

Genome Organization Drives Chromosome Fragility

Abstract

UN SDGs

Keywords

All Science Journal Classification (ASJC) codes

Access to Document

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Cite this