The E3 Ubiquitin Ligase NEDD4L Targets OGG1 for Ubiquitylation and Modulates the Cellular DNA Damage Response

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.

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

The EMBO Journal ◽

10.15252/embj.2019102361 ◽

2019 ◽

Vol 38 (21) ◽

Cited By ~ 5

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

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

Neuro-Oncology ◽

10.1093/neuonc/noz175.195 ◽

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.

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Faculty Opinions recommendation of Activation of the cellular DNA damage response in the absence of DNA lesions.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1108695.571444 ◽

2008 ◽

Author(s):

Yosef Gruenbaum

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Dna Lesions ◽

Damage Response ◽

Cellular Dna

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Targeting Protein-Protein Interactions in the DNA Damage Response Pathways for Cancer Chemotherapy

RSC Chemical Biology ◽

10.1039/d1cb00101a ◽

2021 ◽

Author(s):

Kerry Silva McPherson ◽

Dmitry Korzhnev

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Protein Interactions ◽

Cell Cycle Progression ◽

Protein Protein Interactions ◽

Cycle Progression ◽

Damage Recognition ◽

Damage Response ◽

Cellular Dna ◽

Dna Damage Recognition

Cellular DNA damage response (DDR) is an extensive signaling network that orchestrates DNA damage recognition, repair and avoidance, cell cycle progression and cell death. DDR alternation is a hallmark of...

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Avian Sarcoma and Leukosis Virus Cytopathic Effect in the Absence of TVB Death Domain Signaling

Journal of Virology ◽

10.1128/jvi.79.13.8243-8248.2005 ◽

2005 ◽

Vol 79 (13) ◽

pp. 8243-8248 ◽

Cited By ~ 7

Author(s):

Sara Klucking ◽

Asha S. Collins ◽

John A. T. Young

Keyword(s):

Dna Damage ◽

Signaling Pathways ◽

Dna Damage Response ◽

Cytopathic Effect ◽

Tumor Necrosis Factor Receptor ◽

Death Domain ◽

Trail Receptors ◽

Damage Response ◽

Cellular Dna ◽

Avian Sarcoma

ABSTRACT The cytopathic effect (CPE) seen with some subgroups of avian sarcoma and leukosis virus (ASLV) is associated with viral Env activation of the death-promoting activity of TVB (a tumor necrosis factor receptor-related receptor that is most closely related to mammalian TNF-related apoptosis-inducing ligand [TRAIL] receptors) and with viral superinfection leading to unintegrated viral DNA (UVD) accumulation, which is presumed to activate a cellular DNA damage response. In this study, we employed cells that express signaling-deficient ASLV receptors to demonstrate that an ASLV CPE can be uncoupled from the death-promoting functions of the TVB receptor. However, these cell-killing events were associated with much higher levels of viral superinfection and DNA accumulation than those seen when the virus used signaling-competent TVB receptors. These findings suggest that a putative cellular DNA damage response that is activated by UVD accumulation might act in concert with the death-signaling pathways activated by Env-TVB interactions to trigger cell death. Such a model is consistent with the well-established synergy that exists between TRAIL-signaling pathways and DNA damage responses which is currently being exploited in cancer therapy regimens.

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HPV16-E2 induces prophase arrest and activates the cellular DNA damage response in vitro and in precursor lesions of cervical carcinoma

Oncotarget ◽

10.18632/oncotarget.5512 ◽

2015 ◽

Vol 6 (33) ◽

pp. 34979-34991 ◽

Cited By ~ 6

Author(s):

Yuezhen Xue ◽

Shen Yon Toh ◽

Pingping He ◽

Thimothy Lim ◽

Diana Lim ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Cervical Carcinoma ◽

Precursor Lesions ◽

Damage Response ◽

Cellular Dna

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580. Insight into the Mechanism of Increased Transduction of AAV Vectors with Ad Proteins E1B55k/E4orf6 and Generalization to Other Substrates of the Cellular DNA Damage Response Pathway

Molecular Therapy ◽

10.1016/s1525-0016(16)36384-5 ◽

2012 ◽

Vol 20 ◽

pp. S225

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Damage Response ◽

Cellular Dna ◽

Dna Damage Response Pathway ◽

Insight Into

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High Fidelity Deep Sequencing Reveals No Effect of ATM, ATR, and DNA-PK Cellular DNA Damage Response Pathways on Adenovirus Mutation Rate

Viruses ◽

10.3390/v11100938 ◽

2019 ◽

Vol 11 (10) ◽

pp. 938 ◽

Cited By ~ 1

Author(s):

Risso-Ballester ◽

Sanjuán

Keyword(s):

Dna Damage ◽

Protein Kinase ◽

Dna Damage Response ◽

Deep Sequencing ◽

Molecular Mechanisms ◽

Spontaneous Mutation ◽

High Fidelity ◽

Dna Viruses ◽

Damage Response ◽

Cellular Dna

Most DNA viruses exhibit relatively low rates of spontaneous mutation. However, the molecular mechanisms underlying DNA virus genetic stability remain unclear. In principle, mutation rates should not depend solely on polymerase fidelity, but also on factors such as DNA damage and repair efficiency. Most eukaryotic DNA viruses interact with the cellular DNA damage response (DDR), but the role of DDR pathways in preventing mutations in the virus has not been tested empirically. To address this goal, we serially transferred human adenovirus type 5 in cells in which the telangiectasia-mutated PI3K-related protein kinase (ATM), the ATM/Rad3-related (ATR) kinase, and the DNA-dependent protein kinase (DNA-PK) were chemically inactivated, as well as in control cells displaying normal DDR pathway functioning. High-fidelity deep sequencing of these viral populations revealed mutation frequencies in the order of one-millionth, with no detectable effect of the inactivation of DDR mediators ATM, ATR, and DNA-PK on adenovirus sequence variability. This suggests that these DDR pathways do not play a major role in determining adenovirus genetic diversity.

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