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AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separation.
- Source :
-
Molecular cell [Mol Cell] 2021 Jun 17; Vol. 81 (12), pp. 2596-2610.e7. Date of Electronic Publication: 2021 May 06. - Publication Year :
- 2021
-
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.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- 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
Membrane Proteins physiology
Neoplasm Proteins genetics
Neoplasm Proteins physiology
Signal Transduction physiology
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Tumor Suppressor p53-Binding Protein 1 genetics
Tumor Suppressor p53-Binding Protein 1 physiology
Membrane Proteins metabolism
Neoplasm Proteins metabolism
Tumor Suppressor p53-Binding Protein 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 81
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 33961796
- Full Text :
- https://doi.org/10.1016/j.molcel.2021.04.010