AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separation
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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; Soutoglou, Evi.
I: Molecular Cell, Bind 81, Nr. 12, 2021, s. 2596-2610.e7.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separation
AU - Ghodke, Indrajeet
AU - Remisova, Michaela
AU - Furst, Audrey
AU - Kilic, Sinan
AU - Reina-San-Martin, Bernardo
AU - Poetsch, Anna R.
AU - Altmeyer, Matthias
AU - Soutoglou, Evi
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - DNA-DAMAGE
KW - REPLICATION STRESS
KW - TUMOR-SUPPRESSOR
KW - PROTEIN
KW - G1
KW - ACTIVATION
KW - REPAIR
KW - PROLIFERATION
KW - QUIESCENCE
KW - PROGNOSIS
U2 - 10.1016/j.molcel.2021.04.010
DO - 10.1016/j.molcel.2021.04.010
M3 - Journal article
C2 - 33961796
VL - 81
SP - 2596-2610.e7
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 12
ER -
ID: 275483627