Horizons in Molecular Biology 2017: Right place, right time: novel role of nuclear dynamics in heterochromatic DNA repair

Heterochromatin mostly comprises repeated sequences prone to harmful ectopic recombination during double-strand break (DSB) repair. In Drosophila cells, ‘safe’ homologous recombination (HR) repair of heterochromatic breaks relies on a specialized pathway that relocalizes damaged sequences away from the heterochromatin domain before strand invasion. We discovered that heterochromatic DSBs move to the nuclear periphery to continue HR repair. Relocalization depends on nuclear pores and inner nuclear membrane proteins (INMPs) that anchor repair sites to the nuclear periphery through the Smc5/6-interacting proteins STUbL/RENi. Both the initial block to HR progression inside the heterochromatin domain, and the targeting of repair sites to the nuclear periphery, rely on SUMOylation and three independent SUMO E3 ligases: dPIAS and the Smc5/6 subunits Nse2/Cerv and Nse2/Qjt. We also identified a network of nuclear motors and structural components that promote relocalization by generating directional motions of repair sites. This study reveals a critical role for SUMOylation and motor components in the spatial and temporal regulation of HR repair in heterochromatin, and identifies the nuclear periphery as a specialized site for heterochromatin repair in a multicellular eukaryote.


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