A cohesin/HUSH- and LINC-dependent pathway controls ribosomal DNA double-strand break repair

作者：Aline Marnef, Anne-Laure Finoux, Coline Arnould, Emmanuelle Guillou, Virginie Daburon, Vincent Rocher, Thomas Mangeat, Philippe Mangeot, Emiliano P. Ricci, Gaëlle Legube · 发表于：Genes & Development · 年份：2019 · DOI：10.1101/gad.324012.119 · 被引用次数：116 · 研究领域：DNA Repair Mechanisms、Genomics and Chromatin Dynamics、Nuclear Structure and Function

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.