Localisation of Nup153 and SENP1 to nuclear pore complexes is required for 53BP1 mediated DNA double-strand break repair

Abstract

The nuclear basket of nuclear pore complexes (NPCs) is composed of three nucleoporins: Nup153, Nup50 and Tpr. Nup153 has a role in DNA double-strand break (DSB) repair by promoting nuclear import of 53BP1, a mediator of DNA damage response. Here we provide evidence that loss of Nup153 compromises 53BP1 sumoylation, prerequisite for efficient accumulation of 53BP1 at DSBs. Depletion of Nup153 resulted in reduced SUMO1 modification of 53BP1 and the displacement of the SUMO protease SENP1 from NPCs. Artificial tethering of SENP1 to NPCs restored non-homologous end joining (NHEJ) in the absence of Nup153 and re-established 53BP1 sumoylation. Furthermore, Nup50 and Tpr, the two other nuclear basket nucleoporins, also contribute to proper DSB repair, in a manner distinct from Nup153. Similar to Nup153, Tpr appears implicated in NHEJ and homologous recombination (HR), whereas loss of Nup50 only affected NHEJ. Despite the requirement of all three nucleoporins for accurate NHEJ, only Nup153 is needed for proper nuclear import of 53BP1and SENP1-dependent sumoylation of 53BP1. Our data support the role of Nup153 as important regulator of 53BP1 activity and efficient NHEJ.