A nucleoskeleton network preserves genomic integrity by promoting NHEJ and restraining chromosome translocations

Le résumé fourni par la source

Chromosomal translocation (CT) is characterized by incorrect ligation between chromosome fragments when multiple DNA double-strand breaks (DSBs) exist simultaneously. DNA repair, the three-dimensional structure of the nucleoskeleton, and the spatial and temporal movement of DSB ends contribute to CTs. Our earlier research showed that Intermediate Filament Family Orphan 1 (IFFO1) links the nucleoskeleton and non-homologous end joining (NHEJ) to prevent CTs. In this study, we identified the paralog IFFO2, which, together with IFFO1, forms a complex interaction network. We demonstrate that the C-terminus of these IFFOs binds to XRCC4 to facilitate its participation in the NHEJ process. In contrast, their N-termini oversee the building of the nucleoskeleton by connecting with each other and Lamin A/C. Interestingly, IFFO1 and IFFO2 show epistatic effects in suppressing CT by anchoring broken DNA ends and have non-epistatic roles in NHEJ-mediated DSB repair. Our results define an integrated nucleoskeleton composed of IFFO1-IFFO2-Lamin A/C, and reveal its dual functions in genome stability maintenance, the promotion of end-joining, and the suppression of CT.

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