Trip12 is an E3 ubiquitin ligase for USP7/HAUSP involved in the DNA damage response

FEBS Letters ◽  
2016 ◽  
Vol 590 (23) ◽  
pp. 4213-4222 ◽  
Author(s):  
Xiaoliang Liu ◽  
Xiangcai Yang ◽  
Yongxin Li ◽  
Shuhua Zhao ◽  
Chaocui Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Damage Response

scholarly journals Silencing of E3 Ubiquitin Ligase RNF8 Enhances Ionizing Radiation Sensitivity of Medulloblastoma Cells by Promoting the Deubiquitination of PCNA

2018 ◽  
Vol 26 (9) ◽  
pp. 1365-1373
Author(s):  
Fei Li ◽  
Bin Liu ◽  
Xiaolan Zhou ◽  
Quan Xu
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Dna Damage Response ◽  
Ubiquitin Ligase ◽  
Dna Damage Repair ◽  
E3 Ubiquitin Ligase ◽  
Dna Damage And Repair ◽  
Damage Repair ◽  
Damage Response ◽  
Γ Ray

DNA damage response induced by ionizing radiation (IR) is an important event involved in the sensitivity and efficiency of radiotherapy in human medulloblastoma. RNF8 is an E3 ubiquitin ligase and has key roles in the process of DNA damage and repair. Our study aimed to evaluate the effect of RNF8 in the DNA damage repair induced by IR exposure in medulloblastoma cells. We found that the levels of RNF8 were significantly upregulated by γ-ray irradiation in a dose-dependent manner in medulloblastoma cells and colocalized with γ-H2AX, a sensitive marker of DNA double-strand breaks induced by γ-ray radiation. RNF8 knockdown was observed to enhance the sensitivity of IR in medulloblastoma cells, as evaluated by reduced cell survival. The apoptosis and cell cycle arrest of medulloblastoma cells were dramatically increased by RNF8 suppression after IR treatment. Furthermore, RNF8 inhibition did not affect the protein levels of BRCA1, a crucial protein involved in IR-induced DNA damage repair, but significantly decreased the recruitment of BRCA1 and increased the level of γ-H2AX at DNA damage sites compared to the control. A significant increase in OTM was observed in medulloblastoma cells treated by RNF8 shRNA after exposure to IR, indicating the effect of RNF8 on DNA damage and repair. Additionally, PCNA, a major target for ubiquitin modification during DNA damage response, was found to be monoubiquitinated by E3 ligase RNF8 and might contribute to the low radiosensitivity in medulloblastoma cells. Altogether, our findings may provide RNF8 as a novel target for the improvement of radiotherapy in medulloblastoma.

scholarly journals The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF 8

2019 ◽  
Vol 38 (21) ◽  
Author(s):  
Abhay Narayan Singh ◽  
Judith Oehler ◽  
Ignacio Torrecilla ◽  
Susan Kilgas ◽  
Shudong Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Damage Response

scholarly journals CSIG-25. MTAP LOSS COMPROMISES DNA DAMAGE RESPONSE IN GBM CELLS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi49-vi49
Author(s):  
Changzheng Du ◽  
Landon Hansen ◽  
Simranjit Singh ◽  
Kristen Roso ◽  
Paula Greer ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ubiquitin Ligase ◽  
Cellular Response ◽  
E3 Ubiquitin Ligase ◽  
Genetic Alterations ◽  
Homozygous Deletion ◽  
Signaling Cascade ◽  
Dynamic Interactions ◽  
Damage Response

Abstract Homozygous deletion of methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic alterations in glioblastomas (GBMs), occurring in about half of all patients. Here, we demonstrated that MTAP loss compromises the proteostasis of genomic stability guardian, H2AX, via disrupting a signaling cascade of PRMT5-RNF168-SMURF2. We showed that PRMT5 sustains the expression of RNF168, an E3 ubiquitin ligase essential for cellular response to DNA damage. Suppression of PRMT5 function, as occurring in MTAP-null GBM cells, attenuates the expression of RNF168, which consequently leads to degradation of H2AX protein by a HECT-type E3 ubiquitin ligase, SMURF2. We revealed that RNF168 and SMURF2, serving as a stabilizer and destabilizer of H2AX respectively, functionally oppose each other via their dynamic interactions with H2AX. In supporting the important role of this PRMT5-RNF168-SMURF2 signaling cascade in controlling H2AX homeostasis, MTAP-null GBM cells display a compromised DNA damage response, highlighted by higher levels of DNA damage spontaneously or in response to genotoxic agents. Collectively, these results identify a novel signaling cascade that is essential to the DNA damage response, reveal the profound impact of MTAP loss on GBM cells, and suggest novel therapeutic opportunities.

scholarly journals Exploring the Roles of HERC2 and the NEDD4L HECT E3 Ubiquitin Ligase Subfamily in p53 Signaling and the DNA Damage Response

2021 ◽  
Vol 11 ◽  
Author(s):  
Nicholas A. Mathieu ◽  
Rafael H. Levin ◽  
Donald E. Spratt
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ubiquitin Ligase ◽  
Posttranslational Modifications ◽  
Molecular Mechanisms ◽  
P53 Signaling ◽  
Expression Of Genes ◽  
Genetic Abnormalities ◽  
Damage Response ◽  
Precise Expression

Cellular homeostasis is governed by the precise expression of genes that control the translation, localization, and termination of proteins. Oftentimes, environmental and biological factors can introduce mutations into the genetic framework of cells during their growth and division, and these genetic abnormalities can result in malignant transformations caused by protein malfunction. For example, p53 is a prominent tumor suppressor protein that is capable of undergoing more than 300 posttranslational modifications (PTMs) and is involved with controlling apoptotic signaling, transcription, and the DNA damage response (DDR). In this review, we focus on the molecular mechanisms and interactions that occur between p53, the HECT E3 ubiquitin ligases WWP1, SMURF1, HECW1 and HERC2, and other oncogenic proteins in the cell to explore how irregular HECT-p53 interactions can induce tumorigenesis.

scholarly journals The Role of E3, E4 Ubiquitin Ligase (UBE4B) in Human Pathologies

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 62 ◽  
Author(s):  
Nikolaos Antoniou ◽  
Nefeli Lagopati ◽  
Dimitrios Ilias Balourdas ◽  
Michail Nikolaou ◽  
Alexandros Papalampros ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ubiquitin Ligase ◽  
Molecular Mechanisms ◽  
Ubiquitin Ligases ◽  
Cellular Functions ◽  
P53 Expression ◽  
Damage Response ◽  
Mechanisms Of Carcinogenesis

The genome is exposed daily to many deleterious factors. Ubiquitination is a mechanism that regulates several crucial cellular functions, allowing cells to react upon various stimuli in order to preserve their homeostasis. Ubiquitin ligases act as specific regulators and actively participate among others in the DNA damage response (DDR) network. UBE4B is a newly identified member of E3 ubiquitin ligases that appears to be overexpressed in several human neoplasms. The aim of this review is to provide insights into the role of UBE4B ubiquitin ligase in DDR and its association with p53 expression, shedding light particularly on the molecular mechanisms of carcinogenesis.

scholarly journals Cooperation of HECT-domain Ubiquitin Ligase hHYD and DNA Topoisomerase II-binding Protein for DNA Damage Response

2001 ◽  
Vol 277 (5) ◽  
pp. 3599-3605 ◽  
Author(s):  
Yoshiomi Honda ◽  
Masahide Tojo ◽  
Kazuhito Matsuzaki ◽  
Tadashi Anan ◽  
Mitsuhiro Matsumoto ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ubiquitin Ligase ◽  
Topoisomerase Ii ◽  
Binding Protein ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Hect Domain ◽  
Damage Response

The SUMO-targeted ubiquitin ligase RNF4 localizes to etoposide-exposed mitotic chromosomes: Implication for a novel DNA damage response during mitosis

2014 ◽  
Vol 447 (1) ◽  
pp. 83-88 ◽  
Author(s):  
Masayuki Saito ◽  
Yuka Fujimitsu ◽  
Takeshi Sasano ◽  
Yushi Yoshikai ◽  
Reiko Ban-Ishihara ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ubiquitin Ligase ◽  
Mitotic Chromosomes ◽  
Damage Response

scholarly journals The histone demethylase LSD1/KDM1A promotes the DNA damage response

2013 ◽  
Vol 203 (3) ◽  
pp. 457-470 ◽  
Author(s):  
Nima Mosammaparast ◽  
Haeyoung Kim ◽  
Benoit Laurent ◽  
Yu Zhao ◽  
Hui Jun Lim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ubiquitin Ligase ◽  
Histone Demethylase ◽  
Dependent Manner ◽  
Γ Irradiation ◽  
Histone Demethylation ◽  
Direct Role ◽  
Damage Response ◽  
Histone Ubiquitylation

Histone demethylation is known to regulate transcription, but its role in other processes is largely unknown. We report a role for the histone demethylase LSD1/KDM1A in the DNA damage response (DDR). We show that LSD1 is recruited directly to sites of DNA damage. H3K4 dimethylation, a major substrate for LSD1, is reduced at sites of DNA damage in an LSD1-dependent manner. The E3 ubiquitin ligase RNF168 physically interacts with LSD1 and we find this interaction to be important for LSD1 recruitment to DNA damage sites. Although loss of LSD1 did not affect the initial formation of pH2A.X foci, 53BP1 and BRCA1 complex recruitment were reduced upon LSD1 knockdown. Mechanistically, this was likely a result of compromised histone ubiquitylation preferentially in late S/G2. Consistent with a role in the DDR, knockdown of LSD1 resulted in moderate hypersensitivity to γ-irradiation and increased homologous recombination. Our findings uncover a direct role for LSD1 in the DDR and place LSD1 downstream of RNF168 in the DDR pathway.

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