A cohesin/HUSH- and LINC-dependent pathway controls ribosomal DNA double-strand break repair
A cohesin/HUSH- and LINC-dependent pathway controls ribosomal DNA double-strand break repair
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DOI：
10.1101/gad.324012.119
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发表时间：
2019-09-01
影响因子：
10.5
通讯作者：
Legube, Gaelle
中科院分区：
文献类型：
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作者：
Marnef, Aline;Finoux, Anne-Laure;Legube, Gaelle
核糖体DNA（rDNA）是一个特别不稳定的基因座，经常发生断裂。rDNA内的DNA双链断裂（DSB）诱导rDNA转录抑制和核仁分离，但这两个事件之间的联系尚不清楚。在这里，我们发现在rDNA上诱导的DSB在整个细胞周期中以粘着蛋白和HUSH（人类沉默枢纽）复合物依赖的方式触发转录抑制。在S/G2细胞中，转录抑制进一步继之以核仁内部的延伸切除、核仁帽内核仁周边的DSB动员以及通过同源重组的修复。我们发现，核膜内陷经常连接核仁和rDNA DSB动员，但不是转录抑制，涉及核转录相关LINC复合物和肌动蛋白途径。总之，我们的数据表明，rDNA断裂定位在核仁周边的转录抑制不是一个直接的后果，而是一个积极的过程，共享功能的动员持久的DSB在活性基因和异染色质。
The ribosomal DNA (rDNA) represents a particularly unstable locus undergoing frequent breakage. DNA double-strand breaks (DSBs) within rDNA induce both rDNA transcriptional repression and nucleolar segregation, but the link between the two events remains unclear. Here we found that DSBs induced on rDNA trigger transcriptional repression in a cohesin- and HUSH (human silencing hub) complex-dependent manner throughout the cell cycle. In S/G2 cells, transcriptional repression is further followed by extended resection within the interior of the nucleolus, DSB mobilization at the nucleolar periphery within nucleolar caps, and repair by homologous recombination. We showed that nuclear envelope invaginations frequently connect the nucleolus and that rDNA DSB mobilization, but not transcriptional repression, involves the nuclear envelope-associated LINC complex and the actin pathway. Altogether, our data indicate that rDNA break localization at the nucleolar periphery is not a direct consequence of transcriptional repression but rather is an active process that shares features with the mobilization of persistent DSB in active genes and heterochromatin.