The emerging role of RNA modifications in the regulation of mRNA stability

Experimental & Molecular Medicine, Journal Year: 2020, Volume and Issue: 52(3), P. 400 - 408

Published: March 1, 2020

Many studies have highlighted the importance of tight regulation mRNA stability in control gene expression. largely depends on nucleotide sequence, which affects secondary and tertiary structures mRNAs, accessibility various RNA-binding proteins to mRNAs. Recent advances high-throughput RNA-sequencing techniques resulted elucidation important roles played by modifications sequences regulating stability. To date, hundreds different RNA been characterized. Among them, several modifications, including N

Language: Английский

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N6-methyladenosine-modified circIGF2BP3 inhibits CD8+ T-cell responses to facilitate tumor immune evasion by promoting the deubiquitination of PD-L1 in non-small cell lung cancer

Molecular Cancer, Journal Year: 2021, Volume and Issue: 20(1)

Published: Aug. 20, 2021

Abstract Background An in-depth understanding of immune evasion mechanisms in tumors is crucial to overcome resistance and enable innovative advances immunotherapy. Circular RNAs (circRNAs) have been implicated cancer progression. However, much remains unknown regarding whether circRNAs impact escape non-small-cell lung carcinoma (NSCLC). Methods We performed bioinformatics analysis profile identify the mediating NSCLC. A luciferase reporter assay, RNA immunoprecipitation (RIP), pulldown assays fluorescence situ hybridization were interactions among circIGF2BP3, miR-328-3p, miR-3173-5p plakophilin 3 (PKP3). In vitro T cell-mediated killing vivo syngeneic mouse models used investigate functional roles circIGF2BP3 its downstream target PKP3 antitumor immunity The molecular mechanism PKP3-induced PD-L1 upregulation was explored by immunoprecipitation, RIP, ubiquitination assays. Results demonstrated that (hsa_circ_0079587) expression increased NSCLC negatively correlated with CD8 + cell infiltration. Functionally, elevated inactivated cocultured cells compromised an immunocompetent model, this effect dependent on cells. Mechanistically, METTL3 mediates N 6 -methyladenosine (m A) modification promotes circularization a manner m reader protein YTHDC1. competitively upregulates sponging miR-328-3p compromise response. Furthermore, engages RNA-binding FXR1 stabilize OTUB1 mRNA, elevates abundance facilitating deubiquitination. Tumor deletion completely blocked circIGF2BP3/PKP3 axis inhibition enhanced treatment efficacy anti-PD-1 therapy Lewis model. Collectively, PKP3/PD-L1 signature infiltrating status stratified patients into different risk groups. Conclusion Our results reveal function causing from through decrease subsequent proteasomal degradation stabilizing mRNA PKP3-dependent manner. This work sheds light novel regulation provides rationale enhance

Language: Английский

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Quantitative profiling of pseudouridylation dynamics in native RNAs with nanopore sequencing

Nature Biotechnology, Journal Year: 2021, Volume and Issue: 39(10), P. 1278 - 1291

Published: May 13, 2021

Language: Английский

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N6-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: Nov. 23, 2020

Abstract Background and aims Accumulating evidence suggests that the primary acquired resistance of hepatocellular carcinoma (HCC) to sorafenib is mediated by multiple molecular, cellular, microenvironmental mechanisms. Understanding these mechanisms will enhance likelihood effective therapy. Methods In vitro in vivo experiments were performed clinical samples online databases for investigation. Results this study, we found a circular RNA, circRNA-SORE, which up-regulated so rafenib-resistant HCC cells, was necessary maintenance resistance, silencing circRNA-SORE substantially increased efficacy sorafenib-induced apoptosis. Mechanistic studies determined sequestered miR-103a-2-5p miR-660-3p acting as microRNA sponge, thereby competitively activating Wnt/β-catenin pathway inducing resistance. The level sorafenib-resistant cells resulted from RNA stability. This caused an N 6 -methyladenosine (m A) at specific adenosine circRNA-SORE. delivery interfering local short hairpin lentivirus injection enhanced animal models. Conclusions work indicates novel mechanism maintaining proof-of-concept study targeting sorafenib-treated patients pharmaceutical intervention advanced HCC.

Language: Английский

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Interaction between N6-methyladenosine (m6A) modification and noncoding RNAs in cancer

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: May 22, 2020

As a critical internal RNA modification in higher eukaryotes, N6-methyladenosine (m6A) has become the hotspot of epigenetics research recent years. Extensive studies on messenger RNAs have revealed that m6A affects fate and cell functions various bioprocesses, such as splicing, export, translation, stability, some which seem to be directly or indirectly regulated by noncoding RNAs. Intriguingly, abundant microRNAs, long RNAs, circular small nuclear ribosomal are also highly modified with require for their biogenesis functions. Here, we discuss interaction between focusing functional relevance cancer progression, metastasis, drug resistance, immune response. Furthermore, investigation regulatory proteins its inhibitors provides new opportunities early diagnosis effective treatment cancer, especially combination immunotherapy.

Language: Английский

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RNA modifications: importance in immune cell biology and related diseases

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Sept. 22, 2022

RNA modifications have become hot topics recently. By influencing processes, including generation, transportation, function, and metabolization, they act as critical regulators of cell biology. The immune abnormality in human diseases is also a research focus progressing rapidly these years. Studies demonstrated that participate the multiple biological processes cells, development, differentiation, activation, migration, polarization, thereby modulating responses are involved some related diseases. In this review, we present existing knowledge functions underlying mechanisms modifications, N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), N4-acetylcytosine (ac4C), pseudouridine (Ψ), uridylation, adenosine-to-inosine (A-to-I) editing, summarize their roles Via regulating can pathogenesis diseases, such cancers, infection, inflammatory autoimmune We further highlight challenges future directions based on knowledge. All all, review will provide helpful well novel ideas for researchers area.

Language: Английский

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Quantitative sequencing using BID-seq uncovers abundant pseudouridines in mammalian mRNA at base resolution

Nature Biotechnology, Journal Year: 2022, Volume and Issue: 41(3), P. 344 - 354

Published: Oct. 27, 2022

Abstract Functional characterization of pseudouridine (Ψ) in mammalian mRNA has been hampered by the lack a quantitative method that maps Ψ whole transcriptome. We report bisulfite-induced deletion sequencing (BID-seq), which uses bisulfite-mediated reaction to convert stoichiometrically into upon reverse transcription without cytosine deamination. BID-seq enables detection abundant sites with stoichiometry information several human cell lines and 12 different mouse tissues using 10–20 ng input RNA. uncover consensus sequences for assign ‘writer’ proteins individual deposition. Our results reveal transcript stabilization role installed TRUB1 cancer cells. also detect presence within stop codons confirm promoting codon readthrough vivo. will enable future investigations roles diverse biological processes.

Language: Английский

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Pooled CRISPR screening identifies m ⁶ A as a positive regulator of macrophage activation

Science Advances, Journal Year: 2021, Volume and Issue: 7(18)

Published: April 28, 2021

CRISPR screening identifies RNA m 6 A modification as negative regulator of TLR signaling pathway for proper innate immune response.

Language: Английский

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Targeting the RNA m6A modification for cancer immunotherapy

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: March 16, 2022

Abstract N 6 -methyladenosine (m A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription translation programs that promote cancer occurrence progression. Although defective gene regulation resulting from m A often affects oncogenic tumor-suppressing networks, can also modulate tumor immunogenicity immune cells involved in anti-tumor responses. Understanding this counterintuitive concept aid design new drugs target to potentially improve outcomes immunotherapies. Here, we provide an up-to-date comprehensive overview how modifications intrinsically affect alterations cell extrinsically responses microenvironment (TME). We review strategies for modulating endogenous immunity discuss challenge reshaping TME. Strategies include: combining specific efficient inhibitors against regulators with checkpoint blockers; generating effective programmable gene-editing system enables manipulation individual sites; establishing enhance T or natural killer cells; using nanoparticles specifically tumor-associated macrophages (TAMs) deliver messenger RNA small interfering A-related molecules repolarize TAMs, enabling them remodel The goal help field understand shape TME so better immunotherapy be designed developed.

Language: Английский

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M6A-mediated upregulation of circMDK promotes tumorigenesis and acts as a nanotherapeutic target in hepatocellular carcinoma

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: May 6, 2022

Abstract Background Emerging evidence suggest the critical role of circular RNAs (circRNAs) in disease development especially various cancers. However, oncogenic circRNAs hepatocellular carcinoma (HCC) is still largely unknown. Methods RNA sequencing was performed to identify significantly upregulated paired HCC tissues and non-tumor tissues. CCK-8 assay, colony formation, transwell, xenograft mouse models were used investigate proliferation metastasis. Small interfering (siRNA) silence gene expression. immunoprecipitation, biotin pull-down, luciferase reporter assay western blot explore underlying molecular mechanisms. Results Hsa_circ_0095868 , derived from exon 5 MDK (named circMDK), identified as a new circRNA that HCC. The upregulation circMDK associated with modification N6-methyladenosine (m 6 A) poor survival patients. Mechanistically, sponged miR-346 miR-874-3p upregulate ATG16L1 (Autophagy Related 16 Like 1), resulting activation PI3K/AKT/mTOR signaling pathway promote cell proliferation, migration invasion. Poly (β-amino esters) (PAEs) synthesized assist delivery siRNA (PAE-siRNA), which effectively inhibited tumor progression without obvious adverse effects four liver including subcutaneous, metastatic, orthotopic patient-derived (PDX) models. Conclusions CircMDK could serve potential biomarker promotes via miR-346/874-3p-ATG16L1 axis. PAE-based improved stability efficiency targeting circMDK. PAE-siRNA nanoparticles metastasis vivo. Our current findings offer promising nanotherapeutic strategy for treatment Graphical

Language: Английский

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