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Cell. 2017 Jul 27;170(3):507-521.e18. doi: 10.1016/j.cell.2017.06.034. Epub 2017 Jul 20.

Genome Organization Drives Chromosome Fragility.

Author information

1
Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA.
2
Genomics and Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA.
3
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, NIH, Bethesda, MD, USA.
4
The Center for Genome Architecture, Baylor College of Medicine, Houston, TX, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
5
The Center for Genome Architecture, Baylor College of Medicine, Houston, TX, USA.
6
Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN, USA.
7
Genetics Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
8
Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA. Electronic address: andre_nussenzweig@nih.gov.

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.

KEYWORDS:

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

Comment in

PMID:
28735753
PMCID:
PMC6133249
DOI:
10.1016/j.cell.2017.06.034
[Indexed for MEDLINE]
Free PMC Article

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