Transcriptional mutagenesis mediated by 8-oxoG induces translational errors in mammalian cells

Dai, Da Peng; Gan, Wei; Hayakawa, Hiroshi; Zhu, Jia Lou; Zhang, Xiu Qing; Hu, Guo Xin; Xu, Tao; Jiang, Zhe Li; Zhang, Liqun; Hu, Xue; Nie, Ben; Zhou, Yue; Jin, Li; Zhou, Xiaofeng; Li, Jian; Zhang, Tie Mei; He, Qing; Liu, Dong Ge; Chen, Hai Bo; Yang, Nan; Zuo, Ping; Zhang, Zhi Xin; Yang, Huan; Wang, Yao; Wilson, Samuel H.; Zeng, Yi‐Xin; Wang, Jian Ye; Sekiguchi, Mutsuo; Cai, Jian Ping

doi:10.1073/pnas.1718363115

Cited by 63 publications

(51 citation statements)

References 28 publications

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“…Indeed, Nunomura et al (10) demonstrated that RNA oxidation is a prominent feature of neuronal vulnerability in patients with Alzheimer's disease. More recently, we showed that there is the casual relationship between RNA oxidation and Aβ peptide formation using CHO cells to which 8-oxoGTP is externally supplied (11). Cells carrying 8-oxoG in messenger RNA secreted 28 types of previously unknown Aβ-derived peptides, in addition to a greater amount of pathogenic Aβ peptides that have thus far been characterized.…”

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confidence: 99%

Specific binding of PCBP1 to heavily oxidized RNA to induce cell death

Ishii

Hayakawa

Igawa

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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In aerobically growing cells, the guanine base of RNA is oxidized to 8-oxo-7,8-dihydroguanine (8-oxoG), which induces alteration in their gene expression. We previously demonstrated that the human AUF1 protein binds to 8-oxoG in RNA to induce the selective degradation of oxidized messenger RNA. We herein report that the poly(C)-binding protein PCBP1 binds to more severely oxidized RNA to activate apoptosis-related reactions. While AUF1 binds to oligoribonucleotides carrying a single 8-oxoG, PCBP1 does not bind to such oligoribonucleotides but instead binds firmly to oligoribonucleotides in which two 8-oxoG residues are located nearby. PCBP1-deficient cells, constructed from the human HeLa S3 line using the CRISPR-Cas9 system, exhibited higher survival rates than HeLa S3 cells when small doses of hydrogen peroxide were applied. The levels of caspase-3 activation and PARP-1 cleavage in the PCBP1-deficient cells were significantly lower than those in wild-type cells. The structure-function relationship of PCBP1 was established with the use of PCBP1 mutant proteins in which the conserved KH domains were defective. Human cells appear to possess two distinct mechanisms, one controlled by AUF1 and the other by PCBP1, with the former functioning when messenger RNA is moderately oxidized and the latter operating when the RNA is more severely damaged.

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confidence: 99%

Specific binding of PCBP1 to heavily oxidized RNA to induce cell death

Ishii

Hayakawa

Igawa

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Lastly, another point of relevance relates to the biological impact that oxidative stress has on RNA. Oxidized RNA has been shown to be present in various types of RNA, including rRNA, mRNA, or miRNA, and this also makes riboswitches prone to oxidative damage. Although this relationship has not been established, it is plausible that such processes might play a role in dysfunction or altered regulatory mechanisms.…”

Section: Discussionmentioning

confidence: 99%

7,8‐Dihydro‐8‐oxoguanosine Lesions Inhibit the Theophylline Aptamer or Change Its Selectivity

2020

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Scheme1.Oxidation of Ga tthe C8-positionleads to 8-oxoG. The groupa tthisposition experiences steric hindrance with the C5'-hydrogen atoms, and this induces ac onformational changet ot he syn isomer. Scheme2.A)Sequence of theophylline aptamer and structures of xanthine derivatives. B) Intrastrand/intermolecular interactions (color-coded)that are directly involved in theophylline recognition.Scheme3.Sequences of hairpins 5-8 mimicking the upper scaffold ofthe aptamerand their corresponding T m values (experimentally measured and calculated with UNAFOLD). Conditions: RNA 3.5 mm,NaCl 1mm,MgCl 2 5mm,Na 2 P 2 O 7 10 mm,p H7.2.Scheme4.Representations of RNA aptamer modified at position A) G25 (2/8), or B) G26 (3/9)a nd proposed models of how 8-oxoG might induce aunique tertiarystructure thatdisrupts the binding pocket. C) Plausible structures after modificationa tG11,s howing how 8-oxoG is likely to have ad ifferent, more pronounced, impacto nt he overall structure. Small moleculeConc. range theophylline 11.25 mm-343 nm theobromine 1mm-30 nm caffeine 11.25 mm-343 nm

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“…RNA sequencing of ASDCASK_SS neurons indicated that the mutated T/U is modified to the reference G nucleotide, suggesting that RNA editing is involved in the rescue mechanism. While reports on U-to-G RNA editing are rare, these mechanisms are shown to be relevant for synaptic transcripts and may be involved in the rescue of CASKWT in the ASDCASK_SS (Dai et al, 2018;Reid et al, 2008).…”

Section: Cask-related Disorders Have Emerged As An Important Genetic mentioning

confidence: 99%

“…We have earlier studied pre-and perinatal environmental exposures in the RATSS twin sample, including the ASDCASK_SS case and his co-twin, and showed that uptake of essential metals zinc and manganese, and the neurotoxic metal lead were associated with variable manifestation of autistic traits and ASD diagnoses (Arora et al, 2017). These environmental stressors could potentially affect the RNA processing efficiency and mediate gene-environment interactions leading to differences in outcomes of the twin pair (Dai et al, 2018;Dick et al, 2019;Shomron et al, 2002).…”

Section: Cask-related Disorders Have Emerged As An Important Genetic mentioning

confidence: 99%

Presynaptic dysfunction inCASK-related neurodevelopmental disorders

Becker

Mastropasqua

Reising

et al. 2019

Preprint

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HighlightsModelling of CASK-related disorders using iPSC-derived human neuronal cells CASK mutations cause dysregulation of its protein interactor partners Reduced CASK levels primarily affect inhibitory presynapse development In vitro GABAergic phenotype predicts in vivo neurotransmitter levels Summary (150 words)CASK-related disorders are a genetically defined group of neurodevelopmental syndromes.There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK mutation consequences and neuronal level effects using induced pluripotent stem cell-derived neurons from two mutation carriers; one male diagnosed with ASD and a female with MICPCH. We show a reduction of the CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of gene sets involved in presynaptic development and CASK protein interactors. Furthermore, CASKdeficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory-inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in brain. Our data shows that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.

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Transcriptional mutagenesis mediated by 8-oxoG induces translational errors in mammalian cells

Cited by 63 publications

References 28 publications

Specific binding of PCBP1 to heavily oxidized RNA to induce cell death

Specific binding of PCBP1 to heavily oxidized RNA to induce cell death

7,8‐Dihydro‐8‐oxoguanosine Lesions Inhibit the Theophylline Aptamer or Change Its Selectivity

Presynaptic dysfunction inCASK-related neurodevelopmental disorders

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