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

Abstract

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.

Association of Caspase 3 Activation and H2AX γ Phosphorylation in the Aging Brain: Studies on Untreated and Irradiated Mice

“…Subsequently, the same group demonstrated that neuronal death was blocked in vitro by a pan-caspase inhibitor when cells were irradiated with moderate X-ray doses (≤32 Gray), whereas cell death was unresponsive to caspase inhibition after severe DNA damage (up to 128 Gray) and could occur by non-apoptotic (necrotic) mechanisms [ 26 ]. Very recently, similar results were obtained by another group that studied (in vitro and in vivo) the inhibition of DNA repair pathways in mouse cortical neurons following whole-body irradiation at 10 Grays [ 27 ].…”

“…Irradiation may lead to nerve cell death [ 25 , 26 , 27 ] and initiation of DNA fragmentation during apoptosis, inducing phosphorylation of H2AX [ 28 , 29 ]. Therefore, before addressing the intervention of CASP3 in the response to X-rays, we wanted to ascertain if there were measurable differences in the volumetric cellular density (measured after counting DAPI stained nuclei) among the three groups of experimental mice, i.e., if irradiation was sufficient to induce a massive cellular death within the brief temporal design of our study.…”

“…Therefore, cCASP3 was detected in a small percentage of γH2AX immunoreactive cells, and activation of the caspase did not result in a measurable reduction of the volumetric cellular density in any of the forebrain areas under study ( Appendix D , Figure A4 ). Although to the best of our knowledge there have been no direct observations on the relationship between H2AX phosphorylation and CASP3 activation in the intact aging brain, previous studies have shown that ionizing radiations induce DNA damage and may initiate neuronal apoptosis [ 25 , 26 , 38 , 39 ] with activation of CASP3 [ 27 , 40 ].…”

Adiponectin reduces apoptosis of diabetic cardiomyocytes by regulating miR-711/TLR4 axis

“…MiRNAs have shown significant regulatory effects on cardiac hypertrophy, cardiomyocyte apoptosis, myocardial fibrosis, oxidative stress, and other pathophysiological processes in diabetic cardiomyopathy [26]. miR-711 is a versatile molecule that mediates neuronal apoptosis, neurodegenerative pathways, tumor cell behaviors, and liver injury [27][28][29][30][31][32]. Studies have also reported the role of miR-711 in regulating cardiomyocyte apoptosis.…”

Estrogen associates with female predominance in Xp11.2 translocation renal cell carcinoma

“…Rad54 like 2 ( Rad54l2 ), a paralog of DNA repair and recombination protein Rad54b , participated in super-helical torsion within linear DNA fragments in an ATP-dependent manner 23 . It was widely involved in replication and DNA repair 24 , previous study also reported that Rad54l2 was downregulated after radiotherapy, indicating impaired DNA repair capacity 25 . However, no systemic investigation into its role was carried out in the induction of Xp11.2 tRCC.…”