Genome-wide mapping of long-range contacts unveils clustering of DNA double-strand breaks at damaged active genes.
Genome-wide mapping of long-range contacts unveils clustering of DNA double-strand breaks at damaged active genes.
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DOI：
10.1038/nsmb.3387
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发表时间：
2017-04
影响因子：
16.8
通讯作者：
Legube G
中科院分区：
文献类型：
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作者：
Aymard F;Aguirrebengoa M;Guillou E;Javierre BM;Bugler B;Arnould C;Rocher V;Iacovoni JS;Biernacka A;Skrzypczak M;Ginalski K;Rowicka M;Fraser P;Legube G
DNA双链断裂（DSB）在哺乳动物细胞中聚集的能力在过去几年中一直受到激烈的争论。在这里，我们使用高通量染色体构象捕获分析（Capture Hi-C）来研究在人类基因组中的限定位点处诱导的DSB的聚类。我们明确地发现，DSB集群，但只有在转录活性基因诱导。受损基因的聚集主要发生在G1细胞周期阶段，与延迟修复相一致。此外，DSB聚类依赖于MRN复合物，以及形成蛋白2（FMN 2）核肌动蛋白组织者和LINC（核和细胞质骨架的连接物）复合物，表明活性机制促进DSB聚类。这项工作表明，与基因组的其余部分相比，受损时，活性基因表现出一种非常特殊的行为，大部分未修复并聚集在G1中，同时通过复制后细胞中的同源重组进行修复。
The ability of DNA Double Strand Breaks (DSBs) to cluster in mammalian cells has been subjected to intense debate over the past few 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. We unambiguously found that DSBs do cluster but only when induced in transcriptionally active genes. Clustering of damaged genes mainly occurs 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 LINC (LInker of Nuclear and Cytoplasmic skeleton) complex, suggesting that active mechanisms promote DSB clustering. This work reveals that when damaged, active genes exhibit a very peculiar behavior compared to the rest of the genome, being mostly left unrepaired and clustered in G1 while being repaired by homologous recombination in post-replicative cells.