RAD6B Plays a Critical Role in Neuronal DNA Damage Response to Resist Neurodegeneration

Zhao, Guo; Tian, Yingxia; Guo, Yingli; Li, Boya; Liu, Xiangwen; Xie, Kun; Song, Yanfeng; Wang, Degui

doi:10.3389/fncel.2019.00392

Cited by 16 publications

(7 citation statements)

References 49 publications

(77 reference statements)

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“…DNA damage repair defects that lead to persistent DNA breaks are associated with activation of the neuronal p53/p21 senescence pathways and ultimately neurodegeneration [ 61 ]. In various cells including neurons, the IR-induced senescent phenotype involves a positive feedback loop characterized by p21 WAF1/Cip1 -dependent mitochondrial dysfunction with ROS generation and further DNA damage [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Irradiation-Induced Upregulation of miR-711 Inhibits DNA Repair and Promotes Neurodegeneration Pathways

Sabirzhanov

Makarevich

Barrett

et al. 2020

IJMS

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Radiotherapy for brain tumors induces neuronal DNA damage and may lead to neurodegeneration and cognitive deficits. We investigated the mechanisms of radiation-induced neuronal cell death and the role of miR-711 in the regulation of these pathways. We used in vitro and in vivo models of radiation-induced neuronal cell death. We showed that X-ray exposure in primary cortical neurons induced activation of p53-mediated mechanisms including intrinsic apoptotic pathways with sequential upregulation of BH3-only molecules, mitochondrial release of cytochrome c and AIF-1, as well as senescence pathways including upregulation of p21WAF1/Cip1. These pathways of irradiation-induced neuronal apoptosis may involve miR-711-dependent downregulation of pro-survival genes Akt and Ang-1. Accordingly, we demonstrated that inhibition of miR-711 attenuated degradation of Akt and Ang-1 mRNAs and reduced intrinsic apoptosis after neuronal irradiation; likewise, administration of Ang-1 was neuroprotective. Importantly, irradiation also downregulated two novel miR-711 targets, DNA-repair genes Rad50 and Rad54l2, which may impair DNA damage responses, amplifying the stimulation of apoptotic and senescence pathways and contributing to neurodegeneration. Inhibition of miR-711 rescued Rad50 and Rad54l2 expression after neuronal irradiation, enhancing DNA repair and reducing p53-dependent apoptotic and senescence pathways. Significantly, we showed that brain irradiation in vivo persistently elevated miR-711, downregulated its targets, including pro-survival and DNA-repair molecules, and is associated with markers of neurodegeneration, not only across the cortex and hippocampus but also specifically in neurons isolated from the irradiated brain. Our data suggest that irradiation-induced miR-711 negatively modulates multiple pro-survival and DNA-repair mechanisms that converge to activate neuronal intrinsic apoptosis and senescence. Using miR-711 inhibitors to block the development of these regulated neurodegenerative pathways, thus increasing neuronal survival, may be an effective neuroprotective strategy.

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Section: Discussionmentioning

confidence: 99%

Irradiation-Induced Upregulation of miR-711 Inhibits DNA Repair and Promotes Neurodegeneration Pathways

Sabirzhanov

Makarevich

Barrett

et al. 2020

IJMS

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“…A patient with homozygous mutation in the RNF168 ubiquitin binding domain exhibited mild ataxia-telangiectasia [ 58 ] and mice lacking RNF8 suffer from neuronal degeneration [ 59 ]. Furthermore, mice lacking RAD6B/UBE2B, the E2 ubiquitin-conjugating enzyme for the RING E3 ligase RAD18, have overt neurodegeneration due to a defective response to irradiation-induced DNA damage [ 60 ]. Toxic protein aggregates have been linked with DNA damage in neurodegenerative disease, with ectopic expression of mutant htt promoting extensive histone deubiquitination [ 61 ] and aggregates of p62/SQSTM1 in ALS and FTD able to inhibit the DNA repair ubiquitin ligase RNF168 [ 62 ].…”

Section: Ubiquitin Signalling In the Dna Damage Responsementioning

confidence: 99%

Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities

et al. 2021

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Neurodegenerative diseases are characterised by progressive damage to the nervous system including the selective loss of vulnerable populations of neurons leading to motor symptoms and cognitive decline. Despite millions of people being affected worldwide, there are still no drugs that block the neurodegenerative process to stop or slow disease progression. Neuronal death in these diseases is often linked to the misfolded proteins that aggregate within the brain (proteinopathies) as a result of disease-related gene mutations or abnormal protein homoeostasis. There are two major degradation pathways to rid a cell of unwanted or misfolded proteins to prevent their accumulation and to maintain the health of a cell: the ubiquitin–proteasome system and the autophagy–lysosomal pathway. Both of these degradative pathways depend on the modification of targets with ubiquitin. Aging is the primary risk factor of most neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. With aging there is a general reduction in proteasomal degradation and autophagy, and a consequent increase of potentially neurotoxic protein aggregates of β-amyloid, tau, α-synuclein, SOD1 and TDP-43. An often over-looked yet major component of these aggregates is ubiquitin, implicating these protein aggregates as either an adaptive response to toxic misfolded proteins or as evidence of dysregulated ubiquitin-mediated degradation driving toxic aggregation. In addition, non-degradative ubiquitin signalling is critical for homoeostatic mechanisms fundamental for neuronal function and survival, including mitochondrial homoeostasis, receptor trafficking and DNA damage responses, whilst also playing a role in inflammatory processes. This review will discuss the current understanding of the role of ubiquitin-dependent processes in the progressive loss of neurons and the emergence of ubiquitin signalling as a target for the development of much needed new drugs to treat neurodegenerative disease.

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“…The 3-month-old RNF8 −/− and RNF8 +/+ male mice were used in our studies. The RNF8 −/− mice were provided by Xiaochun Yu as described previously [ 46 ]. The gene-deficient embryonic stem (ES) cell clone RRR260 was used to produce the RNF8 −/− mice.…”

Section: Methodsmentioning

confidence: 99%

RNF8 enhances the sensitivity of PD-L1 inhibitor against melanoma through ubiquitination of galectin-3 in stroma

et al. 2023

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The failure of melanoma immunotherapy can be mediated by immunosuppression in the tumor microenvironment (TME), and insufficient activation of effector T cells against the tumor. Here, we show that inhibition of galectin-3 (gal-3) enhances the infiltration of T cells in TME and improves the sensitivity of anti-PD-L1 therapy. We identify that RNF8 downregulated the expression of gal-3 by K48-polyubiquitination and promoted gal-3 degradation via the ubiquitin–proteasome system. RNF8 deficiency in the host but sufficiency in implanted melanoma results in immune exclusion and tumor progression due to the upregulation of gal-3. Upregulation of gal-3 decreased the immune cell infiltration by restricting IL-12 and IFN-γ. Inhibition of gal-3 reverses immunosuppression and induces immune cell infiltration in the tumor microenvironment. Moreover, gal-3 inhibitor treatment can increase the sensitivity of PD-L1 inhibitors via increasing immune cell infiltration and enhancing immune response in tumors. This study reveals a previously unrecognized immunoregulation function of RNF8 and provides a promising strategy for the therapy of “cold” tumors. Tremendous effects of melanoma treatment can be achieved by facilitating immune cell infiltration combined with anti-PD-L1 treatment.

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RAD6B Plays a Critical Role in Neuronal DNA Damage Response to Resist Neurodegeneration

Cited by 16 publications

References 49 publications

Irradiation-Induced Upregulation of miR-711 Inhibits DNA Repair and Promotes Neurodegeneration Pathways

Irradiation-Induced Upregulation of miR-711 Inhibits DNA Repair and Promotes Neurodegeneration Pathways

Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities

RNF8 enhances the sensitivity of PD-L1 inhibitor against melanoma through ubiquitination of galectin-3 in stroma

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