PIIS1097276521003154.pdf (5.9 MB)
AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separation
Version 2 2023-06-12, 09:47
Version 1 2023-06-09, 23:35
journal contribution
posted on 2023-06-12, 09:47 authored by Indrajeet Ghodke, Michaela Remisova, Audrey Furst, Sinan Kilic, Bernardo Reina-San-Martin, Anna R Poetsch, Matthias Altmeyer, Evi SoutoglouEvi Soutogloup53-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.
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Publication status
- Published
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- Published version
Journal
Molecular CellISSN
1097-2765Publisher
Cell PressExternal DOI
Page range
1-15Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-04-14First Open Access (FOA) Date
2021-05-13First Compliant Deposit (FCD) Date
2021-04-13Usage metrics
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