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

Ghodke, Indrajeet, Remisova, Michaela, Furst, Audrey, Kilic, Sinan, Reina-San-Martin, Bernardo, Poetsch, Anna R, Altmeyer, Matthias and Soutoglou, Evi (2021) AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separation. Molecular Cell. pp. 1-15. ISSN 1097-2765

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Abstract

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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 14 Apr 2021 07:25
Last Modified: 13 May 2021 13:15
URI: http://sro.sussex.ac.uk/id/eprint/98441

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