Genome Organization Drives Chromosome Fragility

Publication date: Available online 20 July 2017
Source:Cell
Author(s): 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
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.

Graphical abstract

Teaser

Chromatin assembly into higher-order structures generates torsional stress that makes chromosome loop anchor regions more vulnerable to topoisomerase 2-mediated DNA breaks.


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