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AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separationGhodke, Indrajeet; Remisova, Michaela; Furst, Audrey; Kilic, Sinan; Reina-San-Martin, Bernardo; Poetsch, Anna R.; Altmeyer, Matthias; Soutoglou, Evi
Molecular cell, 06/2021, Letnik: 81, Številka: 12Journal Article
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. Display omitted •AHNAK is a G1-enriched interactor of 53BP1•AHNAK controls 53BP1-mediated G1-S phase transition upon DNA damage•AHNAK restrains 53BP1 oligomerization and phase separation•AHNAK balances between apoptosis and senescence in cancer and non-transformed cells Ghodke et al. identify the large scaffolding protein AHNAK as a G1-enriched interactor of 53BP1 that ensures optimal partitioning of 53BP1 into phase-separated condensates and limits excessive interaction with p53, which would otherwise lead to apoptosis in cancer cells and senescence in non-transformed cells.
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