The E3 ubiquitin ligase ARIH1 protects against genotoxic stress by initiating a 4EHP-mediated mRNA translation arrest
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The E3 ubiquitin ligase ARIH1 protects against genotoxic stress by initiating a 4EHP-mediated mRNA translation arrest. / von Stechow, Louise; Typas, Dimitris; Carreras Puigvert, Jordi; Oort, Laurens; Siddappa, Ramakrishnaiah; Pines, Alex; Vrieling, Harry; van de Water, Bob; Mullenders, Leon H F; Danen, Erik H J.
I: Molecular and Cellular Biology, Bind 35, Nr. 7, 04.2015, s. 1254-68.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - The E3 ubiquitin ligase ARIH1 protects against genotoxic stress by initiating a 4EHP-mediated mRNA translation arrest
AU - von Stechow, Louise
AU - Typas, Dimitris
AU - Carreras Puigvert, Jordi
AU - Oort, Laurens
AU - Siddappa, Ramakrishnaiah
AU - Pines, Alex
AU - Vrieling, Harry
AU - van de Water, Bob
AU - Mullenders, Leon H F
AU - Danen, Erik H J
N1 - Copyright © 2015, American Society for Microbiology. All Rights Reserved.
PY - 2015/4
Y1 - 2015/4
N2 - DNA damage response signaling is crucial for genome maintenance in all organisms and is corrupted in cancer. In an RNA interference (RNAi) screen for (de)ubiquitinases and sumoylases modulating the apoptotic response of embryonic stem (ES) cells to DNA damage, we identified the E3 ubiquitin ligase/ISGylase, ariadne homologue 1 (ARIH1). Silencing ARIH1 sensitized ES and cancer cells to genotoxic compounds and ionizing radiation, irrespective of their p53 or caspase-3 status. Expression of wild-type but not ubiquitinase-defective ARIH1 constructs prevented sensitization caused by ARIH1 knockdown. ARIH1 protein abundance increased after DNA damage through attenuation of proteasomal degradation that required ATM signaling. Accumulated ARIH1 associated with 4EHP, and in turn, this competitive inhibitor of the eukaryotic translation initiation factor 4E (eIF4E) underwent increased nondegradative ubiquitination upon DNA damage. Genotoxic stress led to an enrichment of ARIH1 in perinuclear, ribosome-containing regions and triggered 4EHP association with the mRNA 5' cap as well as mRNA translation arrest in an ARIH1-dependent manner. Finally, restoration of DNA damage-induced translation arrest in ARIH1-depleted cells by means of an eIF2 inhibitor was sufficient to reinstate resistance to genotoxic stress. These findings identify ARIH1 as a potent mediator of DNA damage-induced translation arrest that protects stem and cancer cells against genotoxic stress.
AB - DNA damage response signaling is crucial for genome maintenance in all organisms and is corrupted in cancer. In an RNA interference (RNAi) screen for (de)ubiquitinases and sumoylases modulating the apoptotic response of embryonic stem (ES) cells to DNA damage, we identified the E3 ubiquitin ligase/ISGylase, ariadne homologue 1 (ARIH1). Silencing ARIH1 sensitized ES and cancer cells to genotoxic compounds and ionizing radiation, irrespective of their p53 or caspase-3 status. Expression of wild-type but not ubiquitinase-defective ARIH1 constructs prevented sensitization caused by ARIH1 knockdown. ARIH1 protein abundance increased after DNA damage through attenuation of proteasomal degradation that required ATM signaling. Accumulated ARIH1 associated with 4EHP, and in turn, this competitive inhibitor of the eukaryotic translation initiation factor 4E (eIF4E) underwent increased nondegradative ubiquitination upon DNA damage. Genotoxic stress led to an enrichment of ARIH1 in perinuclear, ribosome-containing regions and triggered 4EHP association with the mRNA 5' cap as well as mRNA translation arrest in an ARIH1-dependent manner. Finally, restoration of DNA damage-induced translation arrest in ARIH1-depleted cells by means of an eIF2 inhibitor was sufficient to reinstate resistance to genotoxic stress. These findings identify ARIH1 as a potent mediator of DNA damage-induced translation arrest that protects stem and cancer cells against genotoxic stress.
KW - Animals
KW - Carrier Proteins
KW - Caspase 3
KW - Cell Line
KW - Cell Line, Tumor
KW - DNA Damage
KW - Embryonic Stem Cells
KW - Eukaryotic Initiation Factor-4E
KW - Humans
KW - Mice
KW - Protein Biosynthesis
KW - RNA Cap-Binding Proteins
KW - RNA Interference
KW - RNA, Messenger
KW - Tumor Suppressor Protein p53
KW - Ubiquitin-Protein Ligases
KW - Ubiquitination
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1128/MCB.01152-14
DO - 10.1128/MCB.01152-14
M3 - Journal article
C2 - 25624349
VL - 35
SP - 1254
EP - 1268
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
SN - 0270-7306
IS - 7
ER -
ID: 167548883