TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes

Gudjonsson, Thorkell; Altmeyer, Matthias; Savic, Velibor; Toledo, Luis; Dinant, Christoffel; Grøfte, Merete; Bártková, Jiřina; Poulsen, Maria; Oka, Yasuyoshi; Bekker‐Jensen, Simon; Mailand, Niels; Neumann, Beate; Hèriché, Jean-Karim; Shearer, Robert; Saunders, Darren N.; Bártek, Jiří; Lukáš, Jiří; Lukas, Claudia

doi:10.1016/j.cell.2014.11.027

Cited by 63 publications

(104 citation statements)

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“…UbcH7-depleted cells also formed more large 53BP1 foci (Fig. S3A), consistent with a recent report (30). Importantly, overexpression of UbcH7 WT, but not the C86S mutant, reversed the increased 53BP1 foci in UbcH7 depleted cells (Fig.…”

Section: Resultssupporting

confidence: 80%

“…Depletion of UbcH7 was reported to increase the size of 53BP1 foci (30), similar to our observation. Our results suggest that this is likely because UbcH7-depleted cells express elevated levels of 53BP1, allowing the formation of more and larger 53BP1 foci at DSB sites.…”

Section: Discussionsupporting

confidence: 82%

“…UbcH7 can form a complex with BRCA1 in vitro, but failed to support the BRCA1-mediated Ub ligase activity (29). A recent study suggested that depletion of UbcH7 increased 53BP1 retention at DSBs sites (30). However, how exactly UbcH7 regulates DDR and DSB repair is unknown.…”

Section: Resultsmentioning

confidence: 99%

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UbcH7 regulates 53BP1 stability and DSB repair

Han¹,

Zhang²,

Chung³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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DNA double-strand break (DSB) repair is not only key to genome stability but is also an important anticancer target. Through an shRNA library-based screening, we identified ubiquitin-conjugating enzyme H7 (UbcH7, also known as Ube2L3), a ubiquitin E2 enzyme, as a critical player in DSB repair. UbcH7 regulates both the steady-state and replicative stress-induced ubiquitination and proteasome-dependent degradation of the tumor suppressor p53-binding protein 1 (53BP1). Phosphorylation of 53BP1 at the N terminus is involved in the replicative stress-induced 53BP1 degradation. Depletion of UbcH7 stabilizes 53BP1, leading to inhibition of DSB end resection. Therefore, UbcH7-depleted cells display increased nonhomologous end-joining and reduced homologous recombination for DSB repair. Accordingly, UbcH7-depleted cells are sensitive to DNA damage likely because they mainly used the errorprone nonhomologous end-joining pathway to repair DSBs. Our studies reveal a novel layer of regulation of the DSB repair choice and propose an innovative approach to enhance the effect of radiotherapy or chemotherapy through stabilizing 53BP1.DNA damage response | UbcH7 | 53BP1 | protein degradation | DSB repair P rompt response to double-strand breaks (DSBs) caused by, for example, ionization radiation (IR), requires sequential and coordinated assembly of DNA damage response (DDR) proteins at damage sites (1). Recent research findings reveal key roles of the tumor suppressor p53-binding protein 1 (53BP1) and BRCA1 in the decision making of DSB repair. 53BP1, together with Rif1, suppress BRCA1-dependent homologous recombination (HR), thereby promoting nonhomologous end-joining (NHEJ) in G1 phase (2-6). Conversely, BRCA1 antagonizes 53BP1/Rif1, favoring HR in S and G2 phases (7,8). In the absence of BRCA1 or with enhanced retention of 53BP1 at DSB sites, cells primarily use the error-prone NHEJ to repair DSBs throughout the cell cycle, which leads to gene rearrangement, cell death, and increased sensitivity to anticancer therapies (9-11). Consistently, BRCA1-null mice are early embryonic lethal (12, 13) and codepletion of TP53BP1 rescued the lethality phenotype of BRCA1-null mice (12)(13)(14).Low expression level of 53BP1 was found to be associated with poor clinical outcome in triple negative breast cancer patients with BRCA1 mutation (12, 15), as well as resistance to genotoxins and poly(ADP-ribose) polymerase inhibitors (12,16,17). This finding is probably because loss of 53BP1 restored HR and promoted cell survival (12-14). Reduced expression of 53BP1 was also observed in tumors from the brain (18), lymph node (19), and pancreas (20). These data indicate that loss of 53BP1 might be a common mechanism for advanced tumors to evade from radiotherapy or chemotherapy. However, molecular mechanisms controlling the protein level of 53BP1 remain less well understood.Here we show that UbcH7, an E2 enzyme involved in the ubiquitin (Ub) pathway, controls the protein stability of 53BP1, thereby determining the DSB repair choice. Loss of UbcH7 sta...

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Section: Resultssupporting

confidence: 80%

Section: Discussionsupporting

confidence: 82%

See 1 more Smart Citation

UbcH7 regulates 53BP1 stability and DSB repair

Han¹,

Zhang²,

Chung³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Regardless, a subset of UBR5-interacting proteins have been validated as targets of UBR5 E3 Ub ligase activity, although many other interactions appear independent of E3 Ub ligase function, indicating that UBR5-mediated ubiquitination is tightly regulated and is likely context specific. Known targets of UBR5 ligase activity include the DDR proteins TopBP1 (48), RNF168 (49), and ATMIN (42), transcription factors b-catenin (50), pregnane X receptor (PXR; ref. 51), and E6-AP (52), translational machinery CDK9 (53) and PAIP2 (54), the KATNA1 subunit of the cell cycle-related protein KATANIN (55), and the rate limiting enzyme in gluconeogenesis PEPCK (56).…”

Section: Ubr5 Substrates and Other Interacting Proteinsmentioning

confidence: 99%

Functional Roles of the E3 Ubiquitin Ligase UBR5 in Cancer

Shearer

Iconomou

Watts

et al. 2015

Molecular Cancer Research

114

141

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The Ubiquitin-Proteasome System (UPS) is an important regulator of cell signaling and proteostasis, which are essential to a variety of cellular processes. The UPS is disrupted in many diseases including cancer, and targeting the UPS for cancer therapy is gaining wide interest. E3 ubiquitin ligases occupy a key position in the hierarchical UPS enzymatic cascade, largely responsible for determining substrate specificity and ubiquitin (Ub) chain topology. The E3 ligase UBR5 (aka EDD1) is emerging as a key regulator of the UPS in cancer and development. UBR5 expression is deregulated in many cancer types and UBR5 is frequently mutated in mantle cell lymphoma. UBR5 is highly conserved in metazoans, has unique structural features, and has been implicated in regulation of DNA damage response, metabolism, transcription, and apoptosis. Hence, UBR5 is a key regulator of cell signaling relevant to broad areas of cancer biology. However, the mechanism by which UBR5 may contribute to tumor initiation and progression remains poorly defined. This review synthesizes emerging insights from genetics, biochemistry, and cell biology to inform our understanding of UBR5 in cancer. These molecular insights indicate a role for UBR5 in integrating/coordinating various cellular signaling pathways. Finally, we discuss outstanding questions in UBR5 biology and highlight the need to systematically characterize substrates, and address limitations in current animal models, to better define the role of UBR5 in cancer.

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“…To date, many proteins have been identified as ubiquitinated substrates and interacting partners for UBR5, through which UBR5 has been shown to be involved in the various cellular processes such as DNA damage responses (9)(10)(11)(12), cell cycle progression (13-16), the regulation of transcription (17), translation (18) and interleukin-17 (IL-17) production (19). In TH17 cells, DUBA-UBR5 axis regulates the stability of transcription factor RORγt and IL-17 production (19).…”

Section: Micromentioning

confidence: 99%

The p90 ribosomal S6 kinase–UBR5 pathway controls Toll-like receptor signaling via miRNA-induced translational inhibition of tumor necrosis factor receptor–associated factor 3

Cho

Kim

Seo

et al. 2017

Journal of Biological Chemistry

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MicroRNAs (miRNAs) are small, noncodingRNAs that post-transcriptionally regulate gene expression. For example, miRNAs repress gene expression by recruiting the miRNA-induced silencing complex (miRISC), a ribonucleoprotein complex that contains miRNA-engaged Argonaute (Ago) and the scaffold protein GW182. Recently, ubiquitin protein ligase E3 component N-recognin 5 (UBR5) has been identified as a component of miRISC. UBR5 directly interacts with GW182 proteins and participates in miRNA silencing by recruiting downstream effectors, such as the translation regulator DEAD-box helicase 6 (DDX6) and transducer of ERBB2.1/2 (Tob1/2), to the Ago-GW182 complex. However, the regulation of miRISC-associated UBR5 remain largely elusive. In the present study, we show that UBR5 downregulates the levels of TNF receptor-associated factor 3 (TRAF3), a key component of toll-like http://www.jbc.org/cgi

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TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes

Cited by 63 publications

References 0 publications

UbcH7 regulates 53BP1 stability and DSB repair

UbcH7 regulates 53BP1 stability and DSB repair

Functional Roles of the E3 Ubiquitin Ligase UBR5 in Cancer

The p90 ribosomal S6 kinase–UBR5 pathway controls Toll-like receptor signaling via miRNA-induced translational inhibition of tumor necrosis factor receptor–associated factor 3

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