New insight into circRNAs: characterization, strategies, and biomedical applications

Experimental Hematology and Oncology, Год журнала: 2023, Номер 12(1)

Опубликована: Окт. 12, 2023

Abstract Circular RNAs (circRNAs) are a class of covalently closed, endogenous ncRNAs. Most circRNAs derived from exonic or intronic sequences by precursor RNA back-splicing. Advanced high-throughput sequencing and experimental technologies have enabled the extensive identification characterization circRNAs, such as novel types biogenesis, tissue-specific cell-specific expression patterns, epigenetic regulation, translation potential, localization metabolism. Increasing evidence has revealed that participate in diverse cellular processes, their dysregulation is involved pathogenesis various diseases, particularly cancer. In this review, we systematically discuss databases, challenges for circRNA discovery, new insight into strategies used studies biomedical applications. Although recent advanced understanding knowledge approaches annotation, functional applications continuously needed to provide insights circRNAs. The emergence circRNA-based protein strategy will be promising direction field biomedicine.

Язык: Английский

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m6A-regulated tumor glycolysis: new advances in epigenetics and metabolism

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Авг. 15, 2023

Abstract Glycolytic reprogramming is one of the most important features cancer and plays an integral role in progression cancer. In cells, changes glucose metabolism meet needs self-proliferation, angiogenesis lymphangiogenesis, metastasis, also affect immune escape, prognosis evaluation therapeutic effect The n6-methyladenosine (m6A) modification RNA widespread eukaryotic cells. Dynamic reversible m6A modifications are widely involved regulation stem cell renewal differentiation, tumor therapy resistance, microenvironment, metabolism. Lately, more evidences show that can glycolysis process tumors a variety ways to regulate biological behavior tumors. this review, we discussed genesis development, elaborated detail profound impact on different by regulating glycolysis. We believe modified has great significance potential for treatment.

Язык: Английский

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Discovery of a PROTAC degrader for METTL3-METTL14 complex

Cell chemical biology, Год журнала: 2024, Номер 31(1), С. 177 - 183.e17

Опубликована: Янв. 1, 2024

Язык: Английский

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A Stapled Peptide Inhibitor Targeting the Binding Interface of N6‐Adenosine‐Methyltransferase Subunits METTL3 and METTL14 for Cancer Therapy

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(24)

Опубликована: Апрель 12, 2024

METTL3, a primary methyltransferase catalyzing the RNA N6-methyladenosine (m6A) modification, has been identified as an oncogene in several cancer types and thus nominated potentially effective target for therapeutic inhibition. However, current options using this strategy are limited. In study, we targeted protein-protein interactions at METTL3-METTL14 binding interface to inhibit complex formation subsequent catalysis of m6A modification. Among candidate peptides, RM3 exhibited highest anti-cancer potency, inhibiting METTL3 activity while also facilitating its proteasomal degradation. We then designed stapled peptide inhibitor (RSM3) with enhanced stability α-helical secondary structure required interaction. Functional transcriptomic analysis vivo indicated that RSM3 induced upregulation programmed cell death-related genes cancer-promoting signals. Furthermore, tumor growth was significantly suppressed apoptosis upon treatment, accompanied by increased degradation, reduced global methylation levels two models. This exploits mechanism distinct from other small-molecule competitive inhibitors oncogenic activity. Our findings collectively highlight potential targeting therapies through peptide-based inhibition proteolytic

Язык: Английский

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METTL3 protects METTL14 from STUB1‐mediated degradation to maintain m⁶A homeostasis

EMBO Reports, Год журнала: 2023, Номер 24(3)

Опубликована: Янв. 4, 2023

Язык: Английский

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Proteolysis Targeting Chimera Degraders of the METTL3–14 m⁶A-RNA Methyltransferase

JACS Au, Год журнала: 2024, Номер 4(2), С. 713 - 729

Опубликована: Фев. 12, 2024

Methylation of adenine N6 (m6A) is the most frequent RNA modification. On mRNA, it catalyzed by METTL3–14 heterodimer complex, which plays a key role in acute myeloid leukemia (AML) and other types blood cancers solid tumors. Here, we disclose first proteolysis targeting chimeras (PROTACs) for an epitranscriptomics protein. For designing PROTACs, made use crystal structure complex with potent selective small-molecule inhibitor (called UZH2). The optimization linker started from desfluoro precursor UZH2 whose synthesis more efficient than that UZH2. nine PROTAC molecules featured PEG- or alkyl-based linkers, but only latter showed cell penetration. With this information hand, synthesized 26 PROTACs based on alkyl linkers different lengths rigidity. formation ternary was validated FRET-based biochemical assay vitro ubiquitination assay. 14, 20, 22, 24, 30, featuring lengths, 50% higher degradation METTL3 and/or METTL14 measured Western blot MOLM-13 cells. They also substantial three AML lines prostate cancer line PC3.

Язык: Английский

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STUB1/CHIP: New insights in cancer and immunity

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 165, С. 115190 - 115190

Опубликована: Июль 26, 2023

The STUB1 gene (STIP1 homology and U-box-containing protein 1), located at 16q13.3, encodes the CHIP (carboxyl terminus of Hsc70-interacting protein), an essential E3 ligase involved in quality control. comprises three domains: N-terminal tetratricopeptide repeat (TPR) domain, a middle coiled-coil C-terminal U-box domain. It functions as co-chaperone for heat shock (HSP) via TPR domain ligase, ubiquitinating substrates through its Numerous studies suggest that plays crucial role various physiological process, such aging, autophagy, bone remodeling. Moreover, emerging evidence has shown can degrade oncoproteins to exert tumor-suppressive functions, it recently emerged novel player tumor immunity. This review provides comprehensive overview STUB1's cancer, including clinical significance, impact on progression, dual roles, stem cell-like properties, angiogenesis, drug resistance, DNA repair. In addition, we explore immune cell differentiation maturation, inflammation, autoimmunity, antiviral response, Collectively, represents promising valuable therapeutic target cancer immunology.

Язык: Английский

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Emerging importance of m6A modification in liver cancer and its potential therapeutic role

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2025, Номер unknown, С. 189299 - 189299

Опубликована: Март 1, 2025

Язык: Английский

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PRMT1 methylates METTL14 to modulate its oncogenic function

Neoplasia, Год журнала: 2023, Номер 42, С. 100912 - 100912

Опубликована: Июнь 1, 2023

N6-methyladenosine (m6A), the most abundant mRNA modification in mammalian cells, is responsible for stability and alternative splicing. The METTL3-METTL14-WTAP complex only methyltransferase m6A modification. Thus, regulation of its enzymatic activity critical homeostasis levels cells. However, relatively little known about upstream complex, especially at post-translational level. C-terminal RGG repeats METTL14 are RNA binding. Therefore, modifications on these residues may play a regulatory role function. Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs), among which PRMT1 preferentially methylates substrates with an arginine/glycine-rich motif. In addition, functions as key regulator splicing, associated To this end, we report that promotes asymmetric two major C-terminus METTL14, reader SPF30 recognizes Functionally, PRMT1-mediated likely essential function catalyzing Moreover, cell proliferation antagonized inhibitor MS023. These results indicate regulates tumorigenesis through METTL14.

Язык: Английский

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Interconnections between m⁶A RNA modification, RNA structure, and protein–RNA complex assembly

Life Science Alliance, Год журнала: 2023, Номер 7(1), С. e202302240 - e202302240

Опубликована: Ноя. 7, 2023

Protein-RNA complexes exist in many forms within the cell, from stable machines such as ribosome to transient assemblies like spliceosome. All protein-RNA rely on spatially and temporally coordinated interactions between specific proteins RNAs achieve a functional form. RNA folding structure are often critical for successful protein binding complex formation. modifications change chemical nature of given alter its kinetics. Both these alterations can affect how if or other interact with modified assemble into complexes. N

Язык: Английский

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