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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Indrajeet Ghodke
  • Michaela Remisova
  • Audrey Furst
  • Kilic, Sinan
  • Bernardo Reina-San-Martin
  • Anna R. Poetsch
  • Matthias Altmeyer
  • Evi Soutoglou

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.

TidsskriftMolecular Cell
Udgave nummer12
Sider (fra-til)2596-2610.e7
Antal sider23
StatusUdgivet - 2021
Eksternt udgivetJa

ID: 275483627