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

Indrajeet Ghodke (1) , Michaela Remisova (2) , Audrey Furst (1) , Sinan Kilic (2) , Bernardo Reina San Martin (1) , Anna R. Poetsch (3) , Matthias Altmeyer (2) , Evi Soutoglou (1)

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 UZH - Universität Zürich [Zürich] = University of Zurich
3 TU Dresden - Technische Universität Dresden = Dresden University of Technology

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

Mots clés: DNA repair; apoptosis; cancer; cell-cycle progression; p21; p53; phase-separation; senescence; 53BP1; AHNAK

Domaines: Biochimie, Biologie Moléculaire; Cancer

Indrajeet Ghodke, Michaela Remisova, Audrey Furst, Sinan Kilic, Bernardo Reina San Martin, et al.. AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separation. Molecular Cell, 2021, 81 (12), pp.2596-2610. ⟨10.1016/j.molcel.2021.04.010⟩. ⟨hal-03706666⟩