AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separation

Summary p53-binding protein 1 (53BP1) regulates both the DNA damage response and p53 signaling. Although 53BP1's function is well established in double-strand break repair, how its role signaling modulated remains poorly understood. Here, we identify scaffolding AHNAK as a G1 phase-enriched interactor of 53BP1. We demonstrate that binds to 53BP1 oligomerization domain controls multimerization potential. Loss results hyper-accumulation on chromatin enhanced phase separation, culminating an elevated response, compromising cell survival cancer cells but leading senescence non-transformed cells. Cancer transcriptome analyses indicate AHNAK-53BP1 cooperation contributes suppression target gene networks tumors loss sensitizes combinatorial treatments. These findings highlight rheostat function, which surveys proliferation by preventing excessive response.