The E3 ubiquitin ligase ARIH1 protects against genotoxic stress by initiating a 4EHP-mediated mRNA translation arrest

Louise von Stechow; Dimitris Typas; Jordi Carreras Puigvert; Laurens Oort; Ramakrishnaiah Siddappa; Alex Pines; Harry Vrieling; Bob van de Water; Leon H F Mullenders; Erik H J Danen

doi:10.1128/mcb.01152-14

The E3 ubiquitin ligase ARIH1 protects against genotoxic stress by initiating a 4EHP-mediated mRNA translation arrest

Louise von Stechow, Dimitris Typas, Jordi Carreras Puigvert, Laurens Oort, Ramakrishnaiah Siddappa, Alex Pines, Harry Vrieling, Bob van de Water, Leon H F Mullenders, Erik H J Danen

18 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Molecular and Cellular Biology
Volume	35
Issue number	7
Pages (from-to)	1254-68
Number of pages	15
ISSN	0270-7306
DOIs	https://doi.org/10.1128/mcb.01152-14
Publication status	Published - Apr 2015
Externally published	Yes

Keywords

Animals
Carrier Proteins
Caspase 3
Cell Line
Cell Line, Tumor
DNA Damage
Embryonic Stem Cells
Eukaryotic Initiation Factor-4E
Humans
Mice
Protein Biosynthesis
RNA Cap-Binding Proteins
RNA Interference
RNA, Messenger
Tumor Suppressor Protein p53
Ubiquitin-Protein Ligases
Ubiquitination
Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1128/mcb.01152-14

https://mcb.asm.org/content/mcb/35/7/1254.full.pdf

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title = "The E3 ubiquitin ligase ARIH1 protects against genotoxic stress by initiating a 4EHP-mediated mRNA translation arrest",

abstract = "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.",

keywords = "Animals, Carrier Proteins, Caspase 3, Cell Line, Cell Line, Tumor, DNA Damage, Embryonic Stem Cells, Eukaryotic Initiation Factor-4E, Humans, Mice, Protein Biosynthesis, RNA Cap-Binding Proteins, RNA Interference, RNA, Messenger, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Ubiquitination, Journal Article, Research Support, Non-U.S. Gov't",

author = "{von Stechow}, Louise and Dimitris Typas and {Carreras Puigvert}, Jordi and Laurens Oort and Ramakrishnaiah Siddappa and Alex Pines and Harry Vrieling and {van de Water}, Bob and Mullenders, {Leon H F} and Danen, {Erik H J}",

year = "2015",

month = apr,

doi = "10.1128/mcb.01152-14",

language = "English",

volume = "35",

pages = "1254--68",

journal = "Molecular and Cellular Biology",

issn = "0270-7306",

publisher = "American Society for Microbiology",

number = "7",

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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

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

SN - 0270-7306

VL - 35

SP - 1254

EP - 1268

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

IS - 7

ER -

The E3 ubiquitin ligase ARIH1 protects against genotoxic stress by initiating a 4EHP-mediated mRNA translation arrest

Abstract

Keywords

UN SDGs

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