8-Oxoguanine: from oxidative damage to epigenetic and epitranscriptional modification

Experimental & Molecular Medicine, Год журнала: 2022, Номер 54(10), С. 1626 - 1642

Опубликована: Окт. 21, 2022

Abstract In pathophysiology, reactive oxygen species control diverse cellular phenotypes by oxidizing biomolecules. Among these, the guanine base in nucleic acids is most vulnerable to producing 8-oxoguanine, which can pair with adenine. Because of this feature, 8-oxoguanine DNA (8-oxo-dG) induces a G > T (C A) mutation cancers, be deleterious and thus actively repaired repair pathways. 8-Oxoguanine RNA (o 8 G) causes problems aberrant quality translational fidelity, thereby it subjected decay pathway. addition oxidative damage, 8-oxo-dG serves as an epigenetic modification that affects transcriptional regulatory elements other modifications. With ability o G•A pairing, alters structural functional RNA–RNA interactions, enabling redirection posttranscriptional regulation. Here, we address production, regulation, function under stress. Primarily, focus on epitranscriptional roles highlights significance redox-mediated gene expression.

Язык: Английский

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APE1/Ref-1 Role in Inflammation and Immune Response

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Фев. 28, 2022

Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional enzyme that essential for maintaining cellular homeostasis. APE1 the major apurinic/apyrimidinic in base excision repair pathway and acts as redox-dependent regulator of several transcription factors, including NF-κB, AP-1, HIF-1α, STAT3. These functions render vital to regulating cell signaling, senescence, inflammatory pathways. In addition cytokine chemokine expression through activation redox sensitive participates other critical processes immune response, production reactive oxygen species class switch recombination. Furthermore, participation active chromatin demethylation, function also regulates some genes, cytokines such TNFα. The multiple make it an pathogenesis diseases, cancer neurological disorders. Therefore, inhibitors have therapeutic potential. highly expressed central nervous system (CNS) tissue homeostasis, its roles neurodegenerative neuroinflammatory diseases been elucidated. This review discusses known innate adaptive immunity, especially CNS, recent evidence role extracellular environment, potential infectious/immune diseases.

Язык: Английский

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Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons

Cells, Год журнала: 2023, Номер 12(14), С. 1895 - 1895

Опубликована: Июль 20, 2023

APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemoresistance through control gene expression by redox-based mechanism. overexpressed serum-secreted in different cancers, representing prognostic predictive promising non-invasive biomarker. Strategies directly targeting functions led to identification inhibitors showing potential therapeutic value, some which are currently clinical trials. Interestingly, evidence indicates novel roles RNA metabolism still not fully understood, including its activity processing damaged chemoresistant phenotypes, regulating onco-miRNA maturation, oxidized decay. Recent data point out role for sorting onco-miRNAs within secreted extracellular vesicles. This review focused on giving portrait pros cons last two decades research aiming at redox or DNA-repair definition targeted therapies cancer. We will discuss new perspectives cancer therapy emerging from unexpected finding miRNA personalized therapy.

Язык: Английский

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APE1 assembles biomolecular condensates to promote the ATR–Chk1 DNA damage response in nucleolus

Nucleic Acids Research, Год журнала: 2022, Номер 50(18), С. 10503 - 10525

Опубликована: Окт. 6, 2022

Multifunctional protein APE1/APEX1/HAP1/Ref-1 (designated as APE1) plays important roles in nuclease-mediated DNA repair and redox regulation transcription. However, it is unclear how APE1 regulates the damage response (DDR) pathways. Here we show that siRNA-mediated APE1-knockdown or inhibitor treatment attenuates ATR-Chk1 DDR under stress conditions multiple immortalized cell lines. Congruently, overexpression (APE1-OE) activates ATR unperturbed conditions, which independent of nuclease functions. Structural functional analysis reveals a direct requirement extreme N-terminal motif within assembly distinct biomolecular condensates vitro DNA/RNA-independent activation DDR. Overexpressed co-localizes with nucleolar NPM1 assembles nucleoli cancer but not non-malignant cells, recruits activator molecules TopBP1 ETAA1. can directly activate to phosphorylate its substrate Chk1 kinase assays. W119R mutant deficient condensation, incapable activating cells vitro. APE1-OE-induced leads compromised ribosomal RNA transcription reduced viability. Taken together, propose mechanisms by

Язык: Английский

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Ionizing radiation responses appear incidental to desiccation responses in the bdelloid rotifer Adineta vaga

BMC Biology, Год журнала: 2024, Номер 22(1)

Опубликована: Янв. 25, 2024

Abstract Background The remarkable resistance to ionizing radiation found in anhydrobiotic organisms, such as some bacteria, tardigrades, and bdelloid rotifers has been hypothesized be incidental their desiccation resistance. Both stresses produce reactive oxygen species cause damage DNA other macromolecules. However, this hypothesis only investigated a few species. Results In study, we analyzed the transcriptomic response of rotifer Adineta vaga low- (X-rays) high- (Fe) LET highlight molecular genetic mechanisms triggered by both stresses. We identified numerous genes encoding antioxidants, but also chaperones, that are constitutively highly expressed, which may contribute protection proteins against oxidative stress during radiation. detected common with over-expression mainly involved repair protein modifications unknown functions were bdelloid-specific. A distinct specific rehydration was found, Late Embryogenesis Abundant proteins, heat shock glucose repressive proteins. Conclusions These results suggest extreme might indeed consequence capacity resist complete desiccation. This study paves way functional experiments on A. targeting promising candidate playing central roles

Язык: Английский

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APE1 condensation in nucleoli of non-cancer cells depends on rRNA transcription and forming G-quadruplex RNA structures

Nucleic Acids Research, Год журнала: 2025, Номер 53(5)

Опубликована: Фев. 27, 2025

Abstract APE1 [apurinic/apyrimidinic (AP) endodeoxyribonuclease 1] is the main endonuclease of base excision repair pathway acting on abasic sites in DNA. an abundant nuclear protein, and improper expression or localization this factor could lead to accumulation toxic DNA intermediates. Altered subcellular distribution are associated with cancer development, suggesting importance a fine-tuning mechanism for activities. Recent works highlighted presence within nucleoli cells ability form biomolecular condensate. However, whether secondary structures ribosomal RNA (rRNA) influence nucleolar remains poorly understood. Since protein overexpression can result artificial accumulation, it imperative have appropriate cellular models study trafficking under physiological conditions. To address issue, we generated murine embryonic stem cell line expressing endogenous fluorescent-tagged APE1. Live-cell imaging demonstrates that requires active rRNA transcription modulated by different genotoxicants. In vitro experiments showed condensate formation depends RNA-forming G-quadruplex relies critical lysine residues. This sheds light mechanisms underlying nucleolus RNA-dependent condensates.

Язык: Английский

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Disordered peptide-based design of intrinsically disordered polymers for biomedical applications

International Journal of Polymer Analysis and Characterization, Год журнала: 2025, Номер unknown, С. 1 - 49

Опубликована: Фев. 10, 2025

Язык: Английский

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RNA Damage and Its Implications in Genome Stability

DNA repair, Год журнала: 2025, Номер 147, С. 103821 - 103821

Опубликована: Март 1, 2025

Язык: Английский

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Nicking Enzyme Assisted Amplification Combined with CRISPR-Cas12a System for One-Pot Sensitive Detection of APE1

The Analyst, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Apurinic/apyrimidinic endonuclease 1 (APE1) is a critical enzyme in the base excision repair (BER) pathway, essential for preserving cellular equilibrium. Variations APE1 activity within blood or tissues can provide significant insights clinical cancer screening and disease diagnosis. Consequently, detection of diagnostics. However, there currently deficiency rapid, straightforward, sensitive methods detection. To address this issue, we developed method that integrates Nicking Enzyme Assisted Amplification (NEAA) with CRISPR-Cas12a signal amplification, enabling one-pot activity. This utilizes NEAA to produce substantial quantity target DNA complementary crRNA, thereby triggering trans-cleavage Cas12a. The activated Cas12a then amplifies emits signals by cleaving reporter probe. Our strategy allows swift precise APE1, only 3 h, threshold × 10-6 U mL-1 linear range 5 0.1 mL-1. It has been effectively utilized biological samples.

Язык: Английский

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The Apurinic/Apyrimidinic Endodeoxyribonuclease 1 is an RNA G-quadruplex binding protein and regulates miR-92b expression in cancer cells

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 22, 2024

Abstract In the last decade, several novel functions of mammalian Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APE1) have been discovered, going far beyond its canonical function as a DNA repair enzyme, unveiling potential roles in cancer development. Indeed, it was shown to be involved G-quadruplex biology and RNA metabolism, most importantly miRNA maturation pathway decay oxidized- or abasic-miRNAs during oxidative stress conditions. Furthermore, recent years non-canonical pathways biogenesis described, with specific focus on guanosine-rich precursors that can form (rG4) structures. this study, we show precursors, dysregulated upon APE1-depletion, contain an rG4 motif their corresponding target genes are upregulated after APE1-depletion. We also show, both by vitro assays using HeLa cell model, APE1 bind regulate folding structure contained pre-miR92b, mechanism strictly dependent critical lysine residues present N-terminal disordered region. depletion cells alters process miR-92b, mainly affecting shuttling between nucleus cytosol. Lastly, bioinformatic analysis APE1-regulated rG4-containing miRNAs supports relevance our findings for biology. Specifically, these exhibit high prognostic significance lung, cervical, liver cancer, suggested involvement cancer-related pathways. Significance Statement highlight undescribed role context G-quadruplexes (rG4), specifically alternative precursors. binds structures modulates folding, through region some catalytic domain. Moreover, showed interesting new regulating accumulation miR-92b nuclear cytosolic compartments, opening perspectives how may exercise function. APE1-depleted motifs significant value tumors, suggesting targets therapy.

Язык: Английский

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