DNA damage triggers tubular endoplasmic reticulum extension to promote apoptosis by facilitating ER-mitochondria signaling

Zheng, Pengli; Chen, Qingzhou; Tian, Xiaoyu; Qian, Nannan; Chai, Peiyuan; Liu, Bing; Hu, Junjie; Blackstone, Craig; Zhu, Daling; Jiang, Teng; Chen, Jianguo

doi:10.1038/s41422-018-0065-z

Cited by 95 publications

(76 citation statements)

References 88 publications

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“…This view is consistent with recent studies that connected using unbiased approaches the pathways involved in maintenance of genome integrity and proteostasis, showing that dysregulation of the DDR resulted in protein aggregation and autophagy induction 30,31 . Moreover, previous work demonstrated that the function and structure of the ER is drastically affected by DNA damaging agents used in chemotherapy 32,33 . Other recent reports suggested that chronic ER stress suppresses DNA repair and sensitizes cancer cells to ionizing radiation and chemotherapy [34][35][36][37] , in addition to enhancing oxidative damage to the DNA 38 .…”

Section: Discussionmentioning

confidence: 99%

Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response

et al. 2020

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The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1α signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1α endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1α to catalyze RIDD. The protective role of IRE1α under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis.

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Section: Discussionmentioning

confidence: 99%

Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response

et al. 2020

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“…A growing body of evidence suggested that mitochondrial-dependent apoptosis is typically initiated by DNA damage which further modulates cellular redox status associated with the cell death mechanism. 35,36 Histone H2AX phosphorylated on serine 139 (γ-H2AX), one of the hallmarks of DNA damage and DNA double-strand breaks (DSB), is modulated through iROS. Thus, to assess the role of CeO 2 in the induction of DNA damage, immunofluorescence study was carried out to detect the phosphorylation of γ-H2AX underlying the foci formation in the nucleus.…”

Section: ■ Introductionmentioning

confidence: 99%

Pro-Oxidant Therapeutic Activities of Cerium Oxide Nanoparticles in Colorectal Carcinoma Cells

et al. 2020

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Given that basal levels of reactive oxygen species (ROS) are higher in cancer cells, there is a growing school of thought that endorses pro-oxidants as potential chemotherapeutic agents. Intriguingly, cerium oxide (CeO 2 ) nanoparticles can manifest either anti-or pro-oxidant activity as a function of differential pH of various subcellular localizations. In an acidic pH environment, for example, in extracellular milieu of cancer cells, CeO 2 would function as a pro-oxidant. Based on this concept, the present study is designed to investigate the pro-oxidant activities of CeO 2 in human colorectal carcinoma cell line (HCT 116). For comparison, we have also studied the effect of ceria nanoparticles on human embryonic kidney (HEK 293) cells. Dose-dependent viability of cancerous as well as normal cells has been assessed by treating them independently with CeO 2 nanoparticles of different concentrations (5−100 μg/mL) in the culture media. The half maximal inhibitory concentration (IC 50 ) of nanoceria for HCT 116 is found to be 50.48 μg/mL while that for the HEK 293 cell line is 92.03 μg/mL. To understand the intricate molecular mechanisms of CeO 2 -induced cellular apoptosis, a series of experiments have been conducted. The apoptosis-inducing ability of nanoceria has been investigated by Annexin V-FITC staining, caspase 3/9 analysis, cytochrome c release, intracellular ROS analysis, and mitochondrial membrane potential analysis using flow cytometry. Experimental data suggest that CeO 2 treatment causes DNA fragmentation through enhanced generation of ROS, which ultimately leads to cellular apoptosis through the p53-dependent mitochondrial signaling pathway.

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“…In addition, growth arrest may result from ER stress-induced regulation of G2/M transition through the eIF2α signaling pathway [41]. This finds confirmation in observations on DNA damage-mediated tubular endoplasmic reticulum extension, promoting apoptosis by the facilitation of ER-mitochondria signaling [42]. Furthermore, the elevated phosphorylation status of eIF2α was accompanied by inhibition of CHOP, a factor activating transcription of murine double minute 2 that targets p53 for degradation and is required for neuroprotection [43].…”

Section: Discussionmentioning

confidence: 75%

Focus on the Role of Klotho Protein in Neuro-Immune Interactions in HT-22 Cells Upon LPS Stimulation

Rusinek

Sołek

Tabęcka-Łonczyńska

et al. 2020

Cells

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Neuroinflammation is defined as the activation of the brain’s innate immune system in response to an inflammatory challenge and is considered to be a prominent feature of neurodegenerative diseases. The contribution of overactivated neuroglial cells to neuroinflammation and neurodegenerative disorders is well documented, however, the role of hippocampal neurons in the neuroinflammatory process remains fragmentary. In this study, we show for the first time, that klotho acts as a signal transducer between pro-survival and pro-apoptotic crosstalk mediated by ER stress in HT-22 hippocampal neuronal cells during LPS challenge. In control HT-22 cells, LPS treatment results in activation of the IRE1α-p38 MAPK pathway leading to increased secretion of anti-inflammatory IL-10, and thus, providing adaptation mechanism. On the other hand, in klotho-deficient HT-22 cells, LPS induces oxi-nitrosative stress and genomic instability associated with telomere dysfunctions leading to p53/p21-mediated cell cycle arrest and, in consequence, to ER stress, inflammation as well as of apoptotic cell death. Therefore, these results indicate that klotho serves as a part of the cellular defense mechanism engaged in the protection of neuronal cells against LPS-mediated neuroinflammation, emerging issues linked with neurodegenerative disorders.

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DNA damage triggers tubular endoplasmic reticulum extension to promote apoptosis by facilitating ER-mitochondria signaling

Cited by 95 publications

References 88 publications

Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response

Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response

Pro-Oxidant Therapeutic Activities of Cerium Oxide Nanoparticles in Colorectal Carcinoma Cells

Focus on the Role of Klotho Protein in Neuro-Immune Interactions in HT-22 Cells Upon LPS Stimulation

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