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

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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 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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Molecular Cell

ISSN

1097-2765

Publisher

Cell Press

Page range

1-15

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2021-04-14

First Open Access (FOA) Date

2021-05-13

First Compliant Deposit (FCD) Date

2021-04-13

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