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Nat Struct Mol Biol. 2017 Apr;24(4):353-361. doi: 10.1038/nsmb.3387. Epub 2017 Mar 6.

Genome-wide mapping of long-range contacts unveils clustering of DNA double-strand breaks at damaged active genes.

Author information

1
LBCMCP, Centre de Biologie Integrative (CBI), CNRS, Université de Toulouse, UT3.
2
Nuclear Dynamics Programme, The Babraham Institute, Cambridge, UK CB22 3AT.
3
Bioinformatic Plateau I2MC, INSERM and University of Toulouse, Toulouse, France.
4
Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw, Poland.
5
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, USA.
#
Contributed equally

Abstract

The ability of DNA double-strand breaks (DSBs) to cluster in mammalian cells has been a subject of intense debate in recent years. Here we used a high-throughput chromosome conformation capture assay (capture Hi-C) to investigate clustering of DSBs induced at defined loci in the human genome. The results unambiguously demonstrated that DSBs cluster, but only when they are induced within transcriptionally active genes. Clustering of damaged genes occurs primarily during the G1 cell-cycle phase and coincides with delayed repair. Moreover, DSB clustering depends on the MRN complex as well as the Formin 2 (FMN2) nuclear actin organizer and the linker of nuclear and cytoplasmic skeleton (LINC) complex, thus suggesting that active mechanisms promote clustering. This work reveals that, when damaged, active genes, compared with the rest of the genome, exhibit a distinctive behavior, remaining largely unrepaired and clustered in G1, and being repaired via homologous recombination in postreplicative cells.

PMID:
28263325
PMCID:
PMC5385132
DOI:
10.1038/nsmb.3387
[Indexed for MEDLINE]
Free PMC Article

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