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dc.contributor.authorSabirzhanov, Boris
dc.contributor.authorMakarevich, Oleg
dc.contributor.authorBarrett, James P
dc.contributor.authorJackson, Isabel L
dc.contributor.authorGlaser, Ethan P
dc.contributor.authorFaden, Alan I
dc.contributor.authorStoica, Bogdan A
dc.date.accessioned2020-08-06T18:09:22Z
dc.date.available2020-08-06T18:09:22Z
dc.date.issued2020-07-23
dc.identifier.urihttp://hdl.handle.net/10713/13495
dc.description.abstractRadiotherapy 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.en_US
dc.description.urihttps://doi.org/10.3390/ijms21155239en_US
dc.language.isoen_USen_US
dc.publisherMDPI AGen_US
dc.relation.ispartofInternational Journal of Molecular Sciencesen_US
dc.subjectMOMPen_US
dc.subjectNoxaen_US
dc.subjectPumaen_US
dc.subjectRad54l2en_US
dc.subjectmicroRNA (miR), Rad50en_US
dc.subjectneuronal apoptosisen_US
dc.subjectradiationen_US
dc.titleIrradiation-Induced Upregulation of miR-711 Inhibits DNA Repair and Promotes Neurodegeneration Pathwaysen_US
dc.typeArticleen_US
dc.identifier.doi10.3390/ijms21155239
dc.identifier.pmid32718090
dc.source.volume21
dc.source.issue15
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countrySwitzerland


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