AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separation.
Cell Line, Tumor
Chromatin
/ metabolism
DNA
/ genetics
DNA Breaks, Double-Stranded
DNA Repair
G1 Phase
/ physiology
Histones
/ metabolism
Humans
MCF-7 Cells
Membrane Proteins
/ genetics
Neoplasm Proteins
/ genetics
Signal Transduction
/ physiology
Tumor Suppressor Protein p53
/ genetics
Tumor Suppressor p53-Binding Protein 1
/ genetics
53BP1
AHNAK
DNA repair
apoptosis
cancer
cell-cycle progression
p21
p53
phase-separation
senescence
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
17 06 2021
17 06 2021
Historique:
received:
27
08
2020
revised:
05
03
2021
accepted:
09
04
2021
pubmed:
8
5
2021
medline:
21
7
2021
entrez:
7
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33961796
pii: S1097-2765(21)00315-4
doi: 10.1016/j.molcel.2021.04.010
pmc: PMC8221568
pii:
doi:
Substances chimiques
AHNAK protein, human
0
Chromatin
0
Histones
0
Membrane Proteins
0
Neoplasm Proteins
0
TP53BP1 protein, human
0
Tumor Suppressor Protein p53
0
Tumor Suppressor p53-Binding Protein 1
0
DNA
9007-49-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2596-2610.e7Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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