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

Aline Marnef (1) , Anne-Laure Finoux (1) , Coline Arnould (1) , Emmanuelle Guillou (1) , Virginie Daburon (1) , Vincent Rocher (1) , Thomas Mangeat (1) , Philippe Mangeot (2) , Emiliano Ricci (3) , Gaëlle Legube (1)

1 LBCMCP - Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération
2 Contrôle traductionnel des ARNm eucaryotes et viraux – Translational control of Eukaryotic and Viral RNAs
3 LBMC UMR 5239 - Laboratoire de biologie et modélisation de la cellule

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.

Mots clés: ribosomal DNA; cohesin; chromatin; DSB repair; LINC; HUSH

Domaines: Biologie moléculaire

Aline Marnef, Anne-Laure Finoux, Coline Arnould, Emmanuelle Guillou, Virginie Daburon, et al.. A cohesin/HUSH- and LINC-dependent pathway controls ribosomal DNA double-strand break repair. Genes and Development, 2019, 33 (17-18), pp.1175-1190. ⟨10.1101/gad.324012.119⟩. ⟨hal-02352375⟩