AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separation.
Fiche publication
Date publication
avril 2021
Journal
Molecular cell
Auteurs
Membres identifiés du Cancéropôle Est :
Dr REINA-SAN-MARTIN Bernardo
Tous les auteurs :
Ghodke I, Remisova M, Furst A, Kilic S, Reina-San-Martin B, Poetsch AR, Altmeyer M, Soutoglou E
Lien Pubmed
Résumé
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
53BP1, AHNAK, DNA repair, apoptosis, cancer, cell-cycle progression, p21, p53, phase-separation, senescence
Référence
Mol Cell. 2021 Apr 29;: