TRIM24 Is a p53-Induced E3-Ubiquitin Ligase That Undergoes ATM-Mediated Phosphorylation and Autodegradation during DNA Damage

AbstractDNA damage prompts a diverse range of alterations to the chromatin landscape. The RNF168 E3 ubiquitin ligase catalyzes the mono-ubiquitination of histone H2A at lysine (K)13/15 (mUb-H2A), forming a binding module for DNA repair proteins. BRCA1 promotes homologous recombination (HR), in part, through its interaction with PALB2, and the formation of a larger BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex. The mechanism by which BRCA1-P is recruited to chromatin surrounding DNA breaks is unclear. In this study, we reveal that an RNF168-governed signaling pathway is responsible for localizing the BRCA1-P complex to DNA damage. Using mice harboring a Brca1CC (coiled coil) mutation that blocks the Brca1-Palb2 interaction, we uncovered an epistatic relationship between Rnf168− and Brca1CC alleles, which disrupted development, and reduced the efficiency of Palb2-Rad51 localization. Mechanistically, we show that RNF168-generated mUb-H2A recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR). Subsequently, BARD1-BRCA1 accumulate PALB2-RAD51 at DNA breaks via the CC domain-mediated BRCA1-PALB2 interaction. Together, these findings establish a series of molecular interactions that connect the DNA damage signaling and HR repair machinery.

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βarrestin-1 regulates DNA repair by acting as an E3-ubiquitin ligase adaptor for 53BP1

Cell Death and Differentiation ◽

10.1038/s41418-019-0406-6 ◽

2019 ◽

Vol 27 (4) ◽

pp. 1200-1213 ◽

Cited By ~ 1

Author(s):

Ainhoa Nieto ◽

Makoto R. Hara ◽

Victor Quereda ◽

Wayne Grant ◽

Vanessa Saunders ◽

...

Keyword(s):

Dna Damage ◽

Ionizing Radiation ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Strand Break ◽

Double Strand Breaks ◽

Dna Double Strand Breaks ◽

Molecular Scaffold ◽

Strand Breaks

Abstract Cellular DNA is constantly under threat from internal and external insults, consequently multiple pathways have evolved to maintain chromosomal fidelity. Our previous studies revealed that chronic stress, mediated by continuous stimulation of the β2-adrenergic-βarrestin-1 signaling axis suppresses activity of the tumor suppressor p53 and impairs genomic integrity. In this pathway, βarrestin-1 (βarr1) acts as a molecular scaffold to promote the binding and degradation of p53 by the E3-ubiquitin ligase, MDM2. We sought to determine whether βarr1 plays additional roles in the repair of DNA damage. Here we demonstrate that in mice βarr1 interacts with p53-binding protein 1 (53BP1) with major consequences for the repair of DNA double-strand breaks. 53BP1 is a principle component of the DNA damage response, and when recruited to the site of double-strand breaks in DNA, 53BP1 plays an important role coordinating repair of these toxic lesions. Here, we report that βarr1 directs 53BP1 degradation by acting as a scaffold for the E3-ubiquitin ligase Rad18. Consequently, knockdown of βarr1 stabilizes 53BP1 augmenting the number of 53BP1 DNA damage repair foci following exposure to ionizing radiation. Accordingly, βarr1 loss leads to a marked increase in irradiation resistance both in cells and in vivo. Thus, βarr1 is an important regulator of double strand break repair, and disruption of the βarr1/53BP1 interaction offers an attractive strategy to protect cells against high levels of exposure to ionizing radiation.

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Rad7 E3 Ubiquitin Ligase Attenuates Polyubiquitylation of Rpn10 and Dsk2 Following DNA Damage in <i>Saccharomyces cerevisiae</i>

Advances in Biological Chemistry ◽

10.4236/abc.2015.57021 ◽

2015 ◽

Vol 05 (07) ◽

pp. 239-254

Author(s):

Joseph M. Benoun ◽

Danielle Lalimar-Cortez ◽

Analila Valencia ◽

Adriana Granda ◽

Destaye M. Moore ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Dna Damage ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase

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ATM Engages Autodegradation of the E3 Ubiquitin Ligase COP1 After DNA Damage

Science ◽

10.1126/science.1127335 ◽

2006 ◽

Vol 313 (5790) ◽

pp. 1122-1126 ◽

Cited By ~ 87

Author(s):

D. Dornan

Keyword(s):

Dna Damage ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase

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Noncanonical E2 Variant-Independent Function of UBC13 in Promoting Checkpoint Protein Assembly

Molecular and Cellular Biology ◽

10.1128/mcb.00987-08 ◽

2008 ◽

Vol 28 (19) ◽

pp. 6104-6112 ◽

Cited By ~ 32

Author(s):

Michael S. Y. Huen ◽

Jun Huang ◽

Jingsong Yuan ◽

Masahiro Yamamoto ◽

Shizuo Akira ◽

...

Keyword(s):

Dna Damage ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Protein Assembly ◽

Ring Domain ◽

Dna Breaks ◽

Focus Formation ◽

Checkpoint Protein ◽

Ubiquitin Ligase Complex ◽

Ubiquitin Conjugating Enzyme

ABSTRACT The E2 ubiquitin-conjugating enzyme UBC13 plays pivotal roles in diverse biological processes. Recent studies have elucidated that UBC13, in concert with the E3 ubiquitin ligase RNF8, propagates the DNA damage signal via a ubiquitylation-dependent signaling pathway. However, mechanistically how UBC13 mediates its role in promoting checkpoint protein assembly and its genetic requirement for E2 variants remain elusive. Here we provide evidence to support the idea that the E3 ubiquitin ligase complex RNF8-UBC13 functions independently of E2 variants and is sufficient in facilitating ubiquitin conjugations and accumulation of DNA damage mediator 53BP1 at DNA breaks. The RNF8 RING domain serves as the molecular platform to anchor UBC13 at the damaged chromatin, where localized ubiquitylation events allow sustained accumulation of checkpoint proteins. Intriguingly, we found that only a group of RING domains derived from E3 ubiquitin ligases, which have been shown to interact with UBC13, enabled UBC13-mediated FK2 and 53BP1 focus formation at DNA breaks. We propose that the RNF8 RING domain selects and loads a subset of UBC13 molecules, distinct from those that exist as heterodimers, onto sites of double-strand breaks, which facilitates the amplification of DNA damage signals.

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The E3 Ubiquitin Ligase ARIH1 Protects against Genotoxic Stress by Initiating a 4EHP-Mediated mRNA Translation Arrest

Molecular and Cellular Biology ◽

10.1128/mcb.01152-14 ◽

2015 ◽

Vol 35 (7) ◽

pp. 1254-1268 ◽

Cited By ~ 15

Author(s):

Louise von Stechow ◽

Dimitris Typas ◽

Jordi Carreras Puigvert ◽

Laurens Oort ◽

Ramakrishnaiah Siddappa ◽

...

Keyword(s):

Dna Damage ◽

Cancer Cells ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Mrna Translation ◽

Genotoxic Stress ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Dependent Manner ◽

Translation Arrest

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.

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In Vitro Enhanced Sensitivity to Cisplatin in D67Y BRCA1 RING Domain Protein

Breast Cancer Basic and Clinical Research ◽

10.4137/bcbcr.s8184 ◽

2011 ◽

Vol 5 ◽

pp. BCBCR.S8184 ◽

Cited By ~ 1

Author(s):

Apichart Atipairin ◽

Adisorn Ratanaphan

Keyword(s):

Dna Damage ◽

Ubiquitin Ligase ◽

Dna Damage Repair ◽

E3 Ubiquitin Ligase ◽

Chemotherapeutic Agents ◽

Ring Domain ◽

Protein Ubiquitination ◽

Damage Repair ◽

Domain Protein

BRCA1 is a tumor suppressor protein involved in maintaining genomic integrity through multiple functions in DNA damage repair, transcriptional regulation, cell cycle checkpoint, and protein ubiquitination. The BRCA1-BARD1 RING complex has an E3 ubiquitin ligase function that plays essential roles in response to DNA damage repair. BRCA1-associated cancers have been shown to confer a hypersensitivity to chemotherapeutic agents. Here, we have studied the functional consequence of the in vitro E3 ubiquitin ligase activity and cisplatin sensitivity of the missense mutation D67Y BRCA1 RING domain. The D67Y BRCA1 RING domain protein exhibited the reduced ubiquitination function, and was more susceptible to the drug than the D67E or wild-type BRCA1 RING domain protein. This evidence emphasized the potential of using the BRCA1 dysfunction as an important determinant of chemotherapy responses in breast cancer.

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