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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. VIDEO ABSTRACT.

SUBMITTER: Canela A

PROVIDER: S-EPMC6133249 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Genome Organization Drives Chromosome Fragility.

Canela Andres A Maman Yaakov Y Jung Seolkyoung S Wong Nancy N Callen Elsa E Day Amanda A Kieffer-Kwon Kyong-Rim KR Pekowska Aleksandra A Zhang Hongliang H Rao Suhas S P SSP Huang Su-Chen SC Mckinnon Peter J PJ Aplan Peter D PD Pommier Yves Y Aiden Erez Lieberman EL Casellas Rafael R Nussenzweig André A

Cell 20170720 3

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 ...[more]

PMID: 28735753

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