Tyrosine Inhibits TyrRS-mediated DNA Repair and Induces Neuronal Oxidative DNA Damage

Abstract Human aging and neurodegenerative diseases accumulate oxidative DNA damage-associated mutations in neurons. Circadian-regulated tyrosine (Tyr) is increased during aging and in Alzheimer’s Disease (AD). Tyr exacerbates the cognitive decline in the elderly and AD patients. Tyrosyl-tRNA synthetase (TyrRS) that activates Tyr for protein synthesis and participates in DNA repair is depleted in the affected brain regions of AD patients through an unknown mechanism. Here, we found that increased Tyr levels decrease the nuclear and neurite levels of TyrRS in neurons and cause oxidative DNA damage. Although Tyr inhibits protein synthesis at the elongation step, dopamine (DA)- a neurotransmitter derived from Tyr increases TyrRS levels. We previously showed that Tyr inhibits TyrRS-mediated activation of poly-ADP-ribose polymerase 1 (PARP1), a modulator of DNA repair. We now found that trans-resveratrol (trans-RSV) that binds to TyrRS mimicking ‘Tyr conformation’ decreases TyrRS, inhibits DNA repair and induces neurotoxicity. Conversely, cis-RSV binds to TyrRS mimicking a ‘Tyr-free conformation,’ increases TyrRS, facilitates DNA repair, and protects neurons against multiple neurotoxic agents in a TyrRS-dependent manner. Our results suggest that increased Tyr levels may have causal effects in human aging and neurocognitive disorders and offer a plausible explanation to divergent results obtained in clinical trials using RSV.

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The transcription-coupled DNA repair-initiating protein CSB promotes XRCC1 recruitment to oxidative DNA damage

Nucleic Acids Research ◽

10.1093/nar/gky579 ◽

2018 ◽

Vol 46 (15) ◽

pp. 7747-7756 ◽

Cited By ~ 17

Author(s):

Hervé Menoni ◽

Franziska Wienholz ◽

Arjan F Theil ◽

Roel C Janssens ◽

Hannes Lans ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Oxidative Dna Damage

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Efficacy and immunogenicity of MultiTEP-based DNA vaccines targeting human α-synuclein: prelude for IND enabling studies

npj Vaccines ◽

10.1038/s41541-021-00424-2 ◽

2022 ◽

Vol 7 (1) ◽

Author(s):

Changyoun Kim ◽

Armine Hovakimyan ◽

Karen Zagorski ◽

Tatevik Antonyan ◽

Irina Petrushina ◽

...

Keyword(s):

Dna Vaccines ◽

Neurodegenerative Disorder ◽

Neuronal Damage ◽

Lewy Bodies ◽

Amyloid Β ◽

The Elderly ◽

Brain Regions ◽

Dependent Manner ◽

Lewy Neurites ◽

The Brain

AbstractAccumulation of misfolded proteins such as amyloid-β (Aβ), tau, and α-synuclein (α-Syn) in the brain leads to synaptic dysfunction, neuronal damage, and the onset of relevant neurodegenerative disorder/s. Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are characterized by the aberrant accumulation of α-Syn intracytoplasmic Lewy body inclusions and dystrophic Lewy neurites resulting in neurodegeneration associated with inflammation. Cell to cell propagation of α-Syn aggregates is implicated in the progression of PD/DLB, and high concentrations of anti-α-Syn antibodies could inhibit/reduce the spreading of this pathological molecule in the brain. To ensure sufficient therapeutic concentrations of anti-α-Syn antibodies in the periphery and CNS, we developed four α-Syn DNA vaccines based on the universal MultiTEP platform technology designed especially for the elderly with immunosenescence. Here, we are reporting on the efficacy and immunogenicity of these vaccines targeting three B-cell epitopes of hα-Syn aa85–99 (PV-1947D), aa109–126 (PV-1948D), aa126–140 (PV-1949D) separately or simultaneously (PV-1950D) in a mouse model of synucleinopathies mimicking PD/DLB. All vaccines induced high titers of antibodies specific to hα-Syn that significantly reduced PD/DLB-like pathology in hα-Syn D line mice. The most significant reduction of the total and protein kinase resistant hα-Syn, as well as neurodegeneration, were observed in various brain regions of mice vaccinated with PV-1949D and PV-1950D in a sex-dependent manner. Based on these preclinical data, we selected the PV-1950D vaccine for future IND enabling preclinical studies and clinical development.

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PML nuclear bodies are recruited to persistent DNA damage lesions in an RNF168-53BP1 dependent manner and contribute to DNA repair

DNA Repair ◽

10.1016/j.dnarep.2019.04.001 ◽

2019 ◽

Vol 78 ◽

pp. 114-127 ◽

Cited By ~ 9

Author(s):

Marketa Vancurova ◽

Hana Hanzlikova ◽

Lucie Knoblochova ◽

Jan Kosla ◽

Dusana Majera ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Nuclear Bodies ◽

Dependent Manner ◽

Pml Nuclear Bodies

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Mutations in CREBBP and EP300 genes affect DNA repair of oxidative damage in Rubinstein-Taybi syndrome cells

Carcinogenesis ◽

10.1093/carcin/bgz149 ◽

2019 ◽

Vol 41 (3) ◽

pp. 257-266

Author(s):

Ilaria Dutto ◽

Claudia Scalera ◽

Micol Tillhon ◽

Giulio Ticli ◽

Gianluca Passaniti ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Genome Stability ◽

Oxidative Dna Damage ◽

Excision Repair ◽

Control Cell ◽

Nuclear Antigen ◽

Autosomal Dominant Disorder ◽

Cell Extracts ◽

Increased Risk

Abstract Rubinstein-Taybi syndrome (RSTS) is an autosomal-dominant disorder characterized by intellectual disability, skeletal abnormalities, growth deficiency and an increased risk of tumors. RSTS is predominantly caused by mutations in CREBBP or EP300 genes encoding for CBP and p300 proteins, two lysine acetyl-transferases (KAT) playing a key role in transcription, cell proliferation and DNA repair. However, the efficiency of these processes in RSTS cells is still largely unknown. Here, we have investigated whether pathways involved in the maintenance of genome stability are affected in lymphoblastoid cell lines (LCLs) obtained from RSTS patients with mutations in CREBBP or in EP300 genes. We report that RSTS LCLs with mutations affecting CBP or p300 protein levels or KAT activity, are more sensitive to oxidative DNA damage and exhibit defective base excision repair (BER). We have found reduced OGG1 DNA glycosylase activity in RSTS compared to control cell extracts, and concomitant lower OGG1 acetylation levels, thereby impairing the initiation of the BER process. In addition, we report reduced acetylation of other BER factors, such as DNA polymerase β and Proliferating Cell Nuclear Antigen (PCNA), together with acetylation of histone H3. We also show that complementation of CBP or p300 partially reversed RSTS cell sensitivity to DNA damage. These results disclose a mechanism of defective DNA repair as a source of genome instability in RSTS cells.

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Dynamic Compartmentalization of Base Excision Repair Proteins in Response to Nuclear and Mitochondrial Oxidative Stress

Molecular and Cellular Biology ◽

10.1128/mcb.01357-08 ◽

2008 ◽

Vol 29 (3) ◽

pp. 794-807 ◽

Cited By ~ 31

Author(s):

Lyra M. Griffiths ◽

Dan Swartzlander ◽

Kellen L. Meadows ◽

Keith D. Wilkinson ◽

Anita H. Corbett ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Dna Repair ◽

Base Excision Repair ◽

Oxidative Dna Damage ◽

Excision Repair ◽

Intracellular Localization ◽

Genotoxic Stress ◽

Mitochondrial Oxidative Stress ◽

Base Excision

ABSTRACT DNAs harbored in both nuclei and mitochondria of eukaryotic cells are subject to continuous oxidative damage resulting from normal metabolic activities or environmental insults. Oxidative DNA damage is primarily reversed by the base excision repair (BER) pathway, initiated by N-glycosylase apurinic/apyrimidinic (AP) lyase proteins. To execute an appropriate repair response, BER components must be distributed to accommodate levels of genotoxic stress that may vary considerably between nuclei and mitochondria, depending on the growth state and stress environment of the cell. Numerous examples exist where cells respond to signals, resulting in relocalization of proteins involved in key biological transactions. To address whether such dynamic localization contributes to efficient organelle-specific DNA repair, we determined the intracellular localization of the Saccharomyces cerevisiae N-glycosylase/AP lyases, Ntg1 and Ntg2, in response to nuclear and mitochondrial oxidative stress. Fluorescence microscopy revealed that Ntg1 is differentially localized to nuclei and mitochondria, likely in response to the oxidative DNA damage status of the organelle. Sumoylation is associated with targeting of Ntg1 to nuclei containing oxidative DNA damage. These studies demonstrate that trafficking of DNA repair proteins to organelles containing high levels of oxidative DNA damage may be a central point for regulating BER in response to oxidative stress.

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Abstract 1761: Breast cancers with compromised DNA repair exhibit selective sensitivity to elesclomol-induced oxidative DNA damage

10.1158/1538-7445.am2012-1761 ◽

2012 ◽

Author(s):

Elizabeth Alli ◽

James M. Ford

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Oxidative Dna Damage ◽

Breast Cancers ◽

Selective Sensitivity

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Exploring the effect of UV-C radiation on earthworm and understanding its genomic integrity in the context of H2AX expression

Scientific Reports ◽

10.1038/s41598-020-77719-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Karthikeyan Subbiahanadar Chelladurai ◽

Jackson Durairaj Selvan Christyraj ◽

Ananthaselvam Azhagesan ◽

Vennila Devi Paulraj ◽

Muralidharan Jothimani ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Primary Response ◽

Coelomic Fluid ◽

Dependent Manner ◽

Perionyx Excavatus ◽

Dna Damages ◽

Highly Sensitive ◽

Evolutionarily Conserved ◽

Uv C

AbstractMaintaining genomic stability is inevitable for organism survival and it is challenged by mutagenic agents, which include ultraviolet (UV) radiation. Whenever DNA damage occurs, it is sensed by DNA-repairing proteins and thereby performing the DNA-repair mechanism. Specifically, in response to DNA damage, H2AX is a key protein involved in initiating the DNA-repair processes. In this present study, we investigate the effect of UV-C on earthworm, Perionyx excavatus and analyzed the DNA-damage response. Briefly, we expose the worms to different doses of UV-C and find that worms are highly sensitive to UV-C. As a primary response, earthworms produce coelomic fluid followed by autotomy. However, tissue inflammation followed by death is observed when we expose worm to increased doses of UV-C. In particular, UV-C promotes damages in skin layers and on the contrary, it mediates the chloragogen and epithelial outgrowth in intestinal tissues. Furthermore, UV-C promotes DNA damages followed by upregulation of H2AX on dose-dependent manner. Our finding confirms DNA damage caused by UV-C is directly proportional to the expression of H2AX. In short, we conclude that H2AX is present in the invertebrate earthworm, which plays an evolutionarily conserved role in DNA damage event as like that in higher animals.

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Yeast Rpn4 Links the Proteasome and DNA Repair via RAD52 Regulation

International Journal of Molecular Sciences ◽

10.3390/ijms21218097 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8097

Author(s):

Daria S. Spasskaya ◽

Nonna I. Nadolinskaia ◽

Vera V. Tutyaeva ◽

Yuriy P. Lysov ◽

Vadim L. Karpov ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Proteasome Inhibition ◽

26S Proteasome ◽

Dependent Manner ◽

Dna Repair Genes ◽

Damage Resistance ◽

Dna Damaging Agents ◽

Mutant Strains ◽

Repair Genes

Environmental and intracellular factors often damage DNA, but multiple DNA repair pathways maintain genome integrity. In yeast, the 26S proteasome and its transcriptional regulator and substrate Rpn4 are involved in DNA damage resistance. Paradoxically, while proteasome dysfunction may induce hyper-resistance to DNA-damaging agents, Rpn4 malfunction sensitizes yeasts to these agents. Previously, we proposed that proteasome inhibition causes Rpn4 stabilization followed by the upregulation of Rpn4-dependent DNA repair genes and pathways. Here, we aimed to elucidate the key Rpn4 targets responsible for DNA damage hyper-resistance in proteasome mutants. We impaired the Rpn4-mediated regulation of candidate genes using the CRISPR/Cas9 system and tested the sensitivity of mutant strains to 4-NQO, MMS and zeocin. We found that the separate or simultaneous deregulation of 19S or 20S proteasome subcomplexes induced MAG1, DDI1, RAD23 and RAD52 in an Rpn4-dependent manner. Deregulation of RAD23, DDI1 and RAD52 sensitized yeast to DNA damage. Genetic, epigenetic or dihydrocoumarin-mediated RAD52 repression restored the sensitivity of the proteasome mutants to DNA damage. Our results suggest that the Rpn4-mediated overexpression of DNA repair genes, especially RAD52, defines the DNA damage hyper-resistant phenotype of proteasome mutants. The developed yeast model is useful for characterizing drugs that reverse the DNA damage hyper-resistance phenotypes of cancers.

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3,4-Dihydroxybenzalacetone (DBL) Prevents Aging-Induced Myocardial Changes in Senescence-Accelerated Mouse-Prone 8 (SAMP8) Mice

Cells ◽

10.3390/cells9030597 ◽

2020 ◽

Vol 9 (3) ◽

pp. 597

Author(s):

Vijayasree V. Giridharan ◽

Vengadeshprabhu Karupppagounder ◽

Somasundaram Arumugam ◽

Yutaka Nakamura ◽

Ashrith Guha ◽

...

Keyword(s):

Dna Damage ◽

Oxidative Dna Damage ◽

Cardiac Fibrosis ◽

Myocardial Dysfunction ◽

The Elderly ◽

Tunel Staining ◽

Inonotus Obliquus ◽

Age Related ◽

Samp8 Mice ◽

Senescence Accelerated Mouse

Aging is a predominant risk factor for the development and progression of cardiovascular complications. Physiologically and anatomically, the heart undergoes numerous changes that result in poor cardiac function in the elderly population. Recently, several studies have provided promising results, confirming the ability of the senescence-accelerated mouse-prone 8 (SAMP8) model to accurately model age-related cardiovascular alterations. In this study, using a murine model of senescence, SAMP8, we aimed to investigate the effect of 3,4-dihydroxybenzalacetone (DBL), a catechol-containing phenylpropanoid derivative isolated from Inonotus obliquus (Chaga), on cardiac aging. DBL was administered at the doses of 10 mg/kg and 20 mg/kg by oral gavage to SAMP8 mice to examine aging-mediated cardiac changes, such as oxidative DNA damage, oxygen radical antioxidant capacity (ORAC) value, fibrosis, inflammation, and apoptosis. The treatment with DBL at both doses significantly reduced aging-mediated oxidative DNA damage, and simultaneously increased the ORAC value in the SAMP8 assay. Cardiac fibrosis was assessed with Azan-Mallory staining, and the number of cardiac remodeling markers was found to be significantly reduced after the treatment with DBL. We also observed a decrease in cardiomyocyte apoptosis as measured by the terminal transferase-mediated dUTP nick end labeling (TUNEL) staining method and the caspase-3 levels in SAMP8 mice compared with senescence-resistant control (SAMR1) mice. The findings from this study suggest that DBL has a potentially beneficial effect on aging-mediated myocardial alterations. Further studies are warranted to confirm the promising potential of this catechol compound against aging-associated myocardial dysfunction.

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