title: Genome-wide mapping of long-range contacts unveils clustering of DNA double-strand breaks at damaged active genes.
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.
authors.affiliation: LBCMCP, Centre de Biologie Integrative (CBI), CNRS, Université de Toulouse, UT3.
authors.forename: François
authors.initials: F
authors.lastname: Aymard
authors.affiliation: LBCMCP, Centre de Biologie Integrative (CBI), CNRS, Université de Toulouse, UT3.
authors.forename: Marion
authors.initials: M
authors.lastname: Aguirrebengoa
authors.affiliation: LBCMCP, Centre de Biologie Integrative (CBI), CNRS, Université de Toulouse, UT3.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Guillou
authors.affiliation: Nuclear Dynamics Programme, The Babraham Institute, Cambridge, UK CB22 3AT.
authors.forename: Biola M
authors.initials: BM
authors.lastname: Javierre
authors.affiliation: LBCMCP, Centre de Biologie Integrative (CBI), CNRS, Université de Toulouse, UT3.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Bugler
authors.affiliation: LBCMCP, Centre de Biologie Integrative (CBI), CNRS, Université de Toulouse, UT3.
authors.forename: Coline
authors.initials: C
authors.lastname: Arnould
authors.affiliation: LBCMCP, Centre de Biologie Integrative (CBI), CNRS, Université de Toulouse, UT3.
authors.forename: Vincent
authors.initials: V
authors.lastname: Rocher
authors.affiliation: Bioinformatic Plateau I2MC, INSERM and University of Toulouse, Toulouse, France.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Iacovoni
authors.affiliation: Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Biernacka
authors.affiliation: Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Skrzypczak
authors.affiliation: Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Ginalski
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, USA.
authors.forename: Maga
authors.initials: M
authors.lastname: Rowicka
authors.affiliation: Nuclear Dynamics Programme, The Babraham Institute, Cambridge, UK CB22 3AT.
authors.forename: Peter
authors.initials: P
authors.lastname: Fraser
authors.affiliation: LBCMCP, Centre de Biologie Integrative (CBI), CNRS, Université de Toulouse, UT3.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Legube
mesh_terms: D002460:Cell Line; D002874:Chromosome Mapping; D016000:Cluster Analysis; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D021901:DNA, Intergenic / Q000235:genetics; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D015894:Genome, Human; D006657:Histones / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D000072417:Protein Domains; D034741:RNA, Small Interfering / Q000378:metabolism; D011995:Recombination, Genetic / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D021901:DNA, Intergenic; C468783:H2AX protein, human; D006657:Histones; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D013629:Tamoxifen; C016601:afimoxifene