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At least 19 recordsLinked to original sources
PubMed2026

Unveiling m7G modification patterns and causal drivers governing intracranial aneurysm rupture risk through multi-omics validation and m7G-MeRIP-seq profiling.

Intracranial aneurysm (IA) rupture causes severe brain hemorrhage with high mortality, yet its molecular drivers remain unclear and better risk prediction is urgently needed. Using transcriptomics, single-cell analysis, and genetic data, we investigated the role of N7-methylguanosine (m7G) RNA modification in IA. We identified distinct m7G modification patterns, validated their methylation features in patient samples, and incorporated these patterns into a machine learning-based rupture prediction model. The presence and characteristics of m7G patterns significantly improved model performance, achieving high predictive accuracy across three independent cohorts (AUC 0.91-0.95). Genetic analyses further identified three causal m7G-related genes (NSUN2, IFIT5, SNUPN), and laboratory experiments confirmed their altered expression and methylation in ruptured aneurysms. Overall, our findings demonstrate that m7G modifications play a key role in IA rupture. The validated prediction model offers strong clinical potential for rupture risk assessment, and the identified genes represent promising therapeutic targets.

Humans↗
PubMed2025

CYFIP1 coordinate with RNMT to induce osteosarcoma cuproptosis via AURKAIP1 m7G modification.

Osteosarcoma (OS) presents challenges due to its genomic instability and complexity, necessitating investigation into its oncogenesis and progression mechanisms. Recent studies have implicated m7G, a post-transcriptional modification, in the development of various cancers. However, research on m7G modification in OS remains limited. This study aimed to explore the impact of m7G modification in OS, focusing on the role and mechanism of CYFIP1, a member of m7G cap binding complexes. Our findings demonstrated prominent anti-OS effects of CYFIP1 in vitro and vivo. Mechanistically, CYFIP1 collaborated with RNMT to induce the m7G methylation of AURKAIP1 mRNA, which resulted in the stability and the increasing translation of AURKAIP1 mRNA. AURKAIP1, a kind of mitochondrial small ribosomal subunit protein, exhibited increased expression, leading to the dysregulation of mitochondrial translation. This, in turn, caused an increase in the expression of FDX1, eventually triggering cuproptosis in OS cells and repressing OS occurrence and progression. In summary, our study identified the CYFIP1/RNMT/AURKAIP1/FDX1 axis as a potential therapeutic target for OS. These insights contribute to OS research and may guide the development of novel treatments for this challenging disease.

Humans↗
PubMed2026

Methyltransferase METTL1 regulates MSC mRNA stability via m7G modification in acute pancreatitis.

Acute pancreatitis (AP) is a serious inflammatory disease with significant morbidity, yet its underlying molecular mechanisms remain incompletely understood. This study reveals a novel epitranscriptomic pathway in AP pathogenesis centered on METTL1-mediated N7-methylguanosine (m7G) RNA modification. We found that METTL1 expression and global m7G levels were significantly elevated in serum from AP patients, pancreatic tissues of sodium taurocholate-induced AP mice, and in vitro models of LPS-polarized macrophages and STC-injured pancreatic acinar cells. Through integrated multi-omics analysis combining m7G methylome mapping and transcriptome profiling, we identified Musculin (MSC) as a key target whose mRNA stability is enhanced by METTL1-mediated m7G modification. Functional experiments demonstrated that MSC upregulation activates TNF signaling through phosphorylation of NF-κB, JNK, and MAPK proteins, thereby promoting macrophage M1 polarization and pancreatic acinar cell injury. The pathological significance of this pathway was confirmed in vivo, where pancreas-targeted knockdown of Mettl1 significantly attenuated AP severity. Furthermore, mechanistic studies using a catalytic-dead METTL1 mutant established that both the methyltransferase activity of METTL1 and subsequent TNF signaling activation are essential for driving inflammatory responses. Our findings delineate a previously unrecognized METTL1-m7G-MSC-TNF signaling axis that promotes AP progression, highlighting the therapeutic potential of targeting METTL1-mediated epitranscriptomic modification in inflammatory diseases.

Animals↗
PubMed2026

Targeting the METTL1/m7G axis as a therapeutic strategy in myeloid leukemia.

N7-methylguanosine (m7G), a prevalent modification in transfer RNAs (tRNAs), is primarily catalyzed by the methyltransferase METTL1. Although growing evidence supports a role for METTL1 in various tumors, its therapeutic potential and precise function in leukemia stem cell (LSC) homeostasis remain largely unexplored. Here, we identify METTL1 as a key regulator of LSC self-renewal and homing within bone marrow (BM) microenvironment through catalyzing m7G formation on a specific tRNA, tRNAPheGAA, thereby promoting leukemogenesis. Mechanistically, METTL1 loss significantly reduces m7G abundance and steady-state levels of tRNAPheGAA, leading to translation suppression and degradation of transcripts enriched with tRNAPheGAA-related codons, such as hematopoietic cell kinase (HCK). Decreased HCK expression disrupts CXCR4 signaling, impairing LSC self-renewal and BM homing. Therapeutically, we characterized a small-molecule METTL1 inhibitor (M1i; NSC137443), through high-throughput screening. Pharmacological inhibition of METTL1 demonstrated potent antitumor efficacy by reducing tRNA m7G levels and disrupting the tRNAPheGAA/HCK/CXCR4 cascade. Notably, targeting METTL1 significantly reduces LSC frequency, delays leukemogenesis, and prolongs survival in multiple acute myeloid leukemia models. Together, our findings establish a previously unrecognized role for METTL1 and its target tRNAPheGAA in LSC homeostasis and provide compelling proof-of-concept evidence that METTL1 is a druggable epitranscriptomic target for antileukemia therapy.

Humans↗
PubMed1977

Detection of methyltransferase activities which modify Gppp G to m7GpppGm in embryonic chick lens.

GpppG was modified to m7 GpppGm by a cytoplasmic extract, prepared from embryonic lens cells, in a reaction mixture which contained S-adenosyl-methionine as methyl group donor. The appearance of m7 GpppGm was a function of time and lens extract concentration. S-adenosyl-homocysteine inhibited both the m7G and Gm modification reactions. Analogues of GpppG, pG, ppG and pppG were relatively ineffective as substrates.

Animals↗
PubMed1979

Chemical evidence for a codon-induced allosteric change in tRNALys involving the 7-methylguanosine residue 46.

[32P]TRNALys, from Escherichia coli, was modified with kethoxal, in the presence and absence of the oligonucleotide codon (A)4. The presence of the codon resulted in a faster modification rate of the tRNA at three guanine sites which were identified by a diagonal fingerprint method. A large increase in the modification rate occurred at the 7-methylguanosine residue 46 (m7G-46) in the presence of the codon: weakly enhanced modification was observed at G-15 and G-57. It is concluded that the formation of a codon-anticodon complex induces, primarily, a conformational change involving disruption of the m7G-46 from the m7G-46 . G-22 . C-13 base triple. Subsequently, the guanines of G-15 and G-57, in the D and T loops, respectively, become slightly more reactive, suggesting a weak tendency for these two interacting arms to unfold. The results are interpreted in terms of an equilibrium between two main conformers, and a third minor one; the possible significance of these conformers in protein biosynthesis, is considered.

Base Sequence↗
PubMed1978

Antibodies distinguishing between intact and alkali-hydrolyzed 7-methylguanosine.

Antibodies specific for intact 7-methylguanosine (m7G) were induced in rabbits and mice by immunization with nucleoside-BSA or nucleoside-hemocyanin conjugates. Since m7G undergoes alkali-catalyzed hydrolytic fission of the purine ring, modifications were made in the procedure for conjugation of m7G to proteins. After periodate oxidation, m7G was incubated with protein at pH 9.1 at 4 degrees C for one hour during which the nucleoside was found to be stable. Reduction of the Schiff base was done with t-butylamine borane for 30 minutes, and the conjugated protein was isolated quickly by gel filtration at pH 7.2. Both rabbits and mice produced antibodies that readily distinguished between the intact and hydrolyzed m7G. Antibody specificity depended largely on the presence of an intact 7-substituted imidazole ring and some cross-reaction occurred with 7-methylinosine. A weaker reaction occurred with ribothymidine and thymidine. Mouse antibodies induced by m7G-hemocyanin showed the highest specificity. They also recognized m7G in the isolated mRNA cap structure m7G(5')ppp(5')A.

Animals↗
PubMed1977

5'-Terminal capping of RNA by guanylyltransferase from HeLa cell nuclei.

A soluble extract prepared from HeLa cell nuclei has been shown to catalyze the 5'-terminal modification of RNA and synthetic polyribonucleotides to form m7G(5')pppA-and m7G(5')-pppG- structures referred to as caps. The reaction involves the transfer of a GMP moiety from GTP to the 5' end of an RNA molecule containing at least two terminal phosphates. Significantly, neither the beta nor the gamma phosphates of GTP are transferred and polynucleotides with no 5'-terminal phosphate or only one are not acceptors. In the absence of methyl donor, G(5')pppA- and G(5')pppG- structures were synthesized, indicating that methylation is not required for guanylylation. Cap formation was considered to occur by the following mechanism: (see article), in which AdoMet is S-adenosylmethionine, AdoHcy is S-adenosylhomocysteine, and (p)ppN- represents either the original 5' end of an RNA molecule or an internal site to which one or more phosphates were added after processing.

Cell Nucleus↗
PubMed1987

Direct analysis of the mini-exon donor RNA of Trypanosoma brucei: detection of a novel cap structure also present in messenger RNA.

The mini-exon, a short segment found at the 5' end of trypanosome mRNAs, is contributed by a small RNA, the mini-exon donor (medRNA). In vivo 32P-labeled medRNA, a set of smaller RNAs related to it, and mRNA, were purified from Trypanosoma brucei by hybrid selection and gel electrophoresis. Using RNA fingerprinting and sequencing techniques, mini-exon oligonucleotides were identified and characterized. We detected a novel 5' terminal capped oligonucleotide present in both medRNA and mRNA. This structure contained m7G and at least four modified nucleotides, not identified previously. If the T. brucei mini-exon has exactly four transcribed nucleotides upstream from its originally designated 5' end, it would begin with the sequence: m7GpppA*A*C*U*AA*CG (asterisks denote modification) and medRNA would be 140 nucleotides long, excluding the m7G residue. The mini-exon contains, and retains during its transfer to mRNA, a novel 5' terminal structure whose presence could confer unique functional attributes.

Animals↗
PubMed2026

tRNA methylation: functional insights and epitranscriptomic regulation.

tRNAs, one of the most conserved and abundant RNAs, are central components of protein synthesis, transferring genetic information from DNA to proteins through a precise base-pairing mechanism. Post-transcriptional modifications of tRNAs by tRNA modifying enzymes are essential for maintaining their normal physiological functions, including methylation, isomerization and glycosylation. tRNA methylation, particularly 1-methyladenosine (m1A), 5-methylcytidine (m5C), and 7-methylguanosine (m7G), are among the most abundant and diverse types of post-transcriptional modifications of tRNA, which promote the stability of tRNA secondary and tertiary structures and allow for proper translation. In addition, tRNA methylation affects the production and function of tsRNA (tRNA-derived small RNA), small fragments of RNA that further regulate gene expression and protein synthesis. In our review, we discuss the relevant biological functions of tRNA methylation, including tRNA stability, protein translation, and tsRNA biogenesis.

RNA, Transfer↗
PubMed1979

Abortive transcription products of vaccinia virus are guanylylated, methylated, and polyadenylylated.

Abortive transcription products were synthesized in vitro by UV-irradiated vaccinia virus particles that were incubated with all four ribonucleoside triphosphates or by unirradiated particles that were incubated in reaction mixtures deficient in CTP or UTP. The RNA sedimented at 4 to 6S in sucrose gradients, suggesting that premature termination had occurred, presumably in one case because the DNA contained UV-induced pyrimidine dimers and in the other case because of ribonucleoside triphosphate was present at limiting concentration for transcription. Nevertheless, the short transcripts were capped, methylated, and polyadenylylated, indicating that neither completion of an RNA chain nor processing from a polycistronic precursor was required for modification of either end of the RNA. In addition, the finding of m7G(5')pppAm and m7G(5')pppGm at the 5' ends of the short RNA molecules implied that transcription was initiated with both ATP and GTP. The presence of the polyadenylic acid tract suggested that a slow-down or cessation of transcription, rather than a specific 3'-terminal sequence, served as a signal for polyadenylylation.

DNA, Viral↗
PubMed2026

A token-pruning framework enables efficient representation of the human genome for RNA modification analysis.

MOTIVATION: Modelling long genomic sequences remains challenging due to extreme sequence length, high redundancy, and the need for biological interpretability. Although Transformer-based architectures have achieved strong performance across genomic tasks, their high computational cost and reliance on fixed tokenization strategies limit their scalability and ability to focus on biologically informative regions. RESULTS: We propose ATSFormer, a token-pruning Transformer framework for efficient and biologically informed genomic sequence modelling. ATSFormer incorporates an attention-guided and parameter-free Adaptive Token Sampling (ATS) module into Transformer layers. Guided by attention-derived importance scores, ATS dynamically retains informative tokens while probabilistically discarding redundant ones, thereby reducing sequence length, FLOPs, and memory usage without introducing additional learnable parameters or extra training procedures. Importantly, the retained tokens correspond to key contributors to model predictions, enabling ATSFormer to highlight biologically meaningful sites and sequence motifs. We evaluated ATSFormer on four benchmark RNA modification datasets derived from RMVar 2.0, covering A-to-I, m1A, m5C, and m7G. Experimental results show that ATSFormer consistently outperforms existing state-of-the-art methods while achieving substantial computational savings. Furthermore, structural analysis using AlphaFold3 supports the biological relevance of the motifs identified by ATSFormer. AVAILABILITY AND IMPLEMENTATION: The source data and code are freely available at GitHub (https://github.com/1gao2/ATSFormer) and Zenodo (https://doi.org/10.5281/zenodo.21813541).

Humans↗
PubMed1990

The methylation of one specific guanosine in a pre-tRNA prevents cleavage by RNase P and by the catalytic M1 RNA.

Several modified nucleosides were introduced during in vitro RNA synthesis into a pre-tRNA(Ser). The pre-tRNAs were used as substrates for RNase P enzymes. No effects were observed with biotin-8-ATP or [alpha-S]-GPT, whereas with m7GTP, the cleavage reaction was completely inhibited. Analysis of pre-tRNAs which contained m7G at various positions has revealed a single base at the 5'-end of the acceptor stem where this modification absolutely prevents cleavage by catalytic M1 RNA, eukaryotic and prokaryotic RNase P holoenzymes. These results suggest that a critical contact must be made between pre-tRNA substrate and enzyme/ribozyme or that the approach of the potential cleaving agent (a positive magnesium ion) is made impossible by the positive charge at N-7 of the guanosine. In addition, we have shown that a pre-tRNA containing only m7G's can still form a complex with M1 RNA in a gel retardation assay.

Base Sequence↗
PubMed2026

Epigenetic alterations induced by ionizing radiation: pathways to cancer and prognostic strategies.

PURPOSE: Ionizing radiation (IR) is widely used not only in cancer diagnosis and therapy, but its biological effects also extend beyond radiation-induced lethal lesions, e.g., specifically DNA double-strand breaks (DNA-DSBs). This review aims to summarize current evidence on IR-induced epigenetic alterations and to integrate mechanistic insights from radiation chemistry and radiation biology that link DNA damage to long-term epigenetic dysregulation. RESULTS: Experimental and clinical studies collectively show that IR induces persistent epigenetic reprogramming, including global and gene-specific DNA methylation changes, radiation-responsive histone modifications, chromatin remodeling, and dysregulation of non-coding RNAs. Aberrant RNA methylation, including modifications like N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanine (m7G), and N3-methylcytosine (m3C), is closely linked to tumorigenesis and progression. Due to its tumor-specific properties, RNA methylation markers, specifically m6A, m5C, m1A, m7G, and m3C, emerge as valuable markers in liquid biopsy. Radiation chemistry studies indicate that epigenetically modified bases, for example, m5C, are preferential targets of radiation-induced oxidative damage, thereby promoting mutational hotspots and genomic instability. By altering DNA repair, apoptosis, immune responses, and cellular differentiation, these epigenetic changes promote carcinogenesis, radioresistance, and tissue toxicity. CONCLUSION: IR-induced epigenetic alterations represent a critical interface between initial DNA damage and long-term biological outcomes. Improved understanding of radiation-associated epigenetic signatures may enhance risk assessment, inform prognostic stratification, and support the development of epigenetic-targeted strategies to optimize radiotherapy and reduce adverse effects.

Ionizing radiation↗
PubMed1987

Ribosomal RNA methylation in Mycobacterium smegmatis SN2.

Ribosomal RNA (rRNA) from a fast growing nonpathogenic strain of mycobacteria, Mycobacterium smegmatis SN2, was analyzed for the presence of minor nucleotides. Of the sixteen modified nucleotides detected, the identity of twelve has been established and their molar ratios were determined. These nucleotides include m1A, m2A, m6A, m6(2)A, m7G, m5C, rT, CmpC, CmpG, GmpG, UmpG and UmpU. The distinct features of the mycobacterial rRNA modifications include: (i) relatively substantial level of methylation, a feature distinct from that of the tRNA species which are unique in being under methylated in these bacteria, (ii) N1 methyl adenine representing the bulk of the modified bases, (iii) the lack of ribose methylation on any two successive nucleotides, and (iv) the presence of N6,N6-dimethyl adenosines, which are the target sites of the antibiotic kasugamycin, although the bacterial growth is insensitive to the drug.

Carbon Radioisotopes↗
PubMed1978

mRNA(nucleoside-2'-)-methyltransferase from vaccinia virus. Purification and physical properties.

An S-adenosyl-L-methionine:mRNA(nucleoside-2'-)-methyltransferase, one of at least three activities required for the 5'-terminal modification of mRNA, has been purified from vaccinia virus particles. Employing brome mosaic virus RNA ending in m7G(5')pppG- as substrate, a simple DEAE-cellulose filter assay measuring the incorporation of methyl groups from S-adenosyl[methyl-3H]methionine to position 2' of the penultimate nucleoside was devised. Starting from disrupted vaccinia virus cores, a 350-fold enzyme purification was achieved by successive chromatography on columns of DEAE-cellulose, CM-Sephadex, and APP-agarose. Analysis of the isolated enzyme by sodium dodecyl sulfate-polyacrylamide discontinuous gel electrophoresis revealed a single polypeptide with a molecular weight of 38,000. Similar molecular weights were obtained by sucrose gradient centrifugation and gel filtration of the native methyltransferase. The isoelectric point of the purified enzyme occurs at pH 8.4.

Methyltransferases↗
PubMed1976

Modification of the 5' terminus of mRNA by an RNA (guanine-7-)-methyltransferase from HeLa cells.

The 5' termini of many viral and cellular mRNAs contain sequences of the type m7G(5")pppNm. An RNA (guanine-7-)-methyltransferase that specifically methylates the 5'-terminal guanosine residue of RNAs ending in the dinucleoside triphosphate G(5')pppN- has been purified from the cytoplasm of HeLa cells. Approximately two-thirds of the methyltransferase activity detected in an assay employing umnethylated vaccinia virus mRNA as acceptor was located in the cytoplasm when cells were disrupted by Dounce homogenization; 30% of the cytoplasmic activity was associated with ribosomes but was removed by washing with 0.5 M KCl. The enzyme was purified 165-fold from the cytoplasm by removing nucleic acid by phase partition followed by ammonium sulfate precipitation and column chromatography on DEAE-cellulose, denatured DNA-agarose, and CM-Sephadex. The partially purified enzyme preparation methylated heterologous tRNAs as well as vaccinia mRNA, but the tRNA methyltransferases could be separated from the mRNA activity by sucrose gradient sedimentation and gel filtration on Sephadex G-200. The product of the partially purified enzyme using vaccinia mRNA as substrate was exclusively 7-methylguanosine located in the terminal dinucleoside triphosphate. In addition to RNAs and synthetic polyribonucleotides terminating in a dinucleoside triphosphate, free G(5')pppG could be methylated but GTP, GDP, and G(5')pppG could not. The enzyme also methylated the dinucleoside diphosphate G(5')pppG but much less efficiently than G(5')pppG. An S20, W of 3.8, a Stokes radius of 3.6 nm, and a molecular weight of 56,000 were obtained from sucrose gradient sedimentation and Sephadex G-200 column chromatography.

Base Sequence↗
PubMed1975

Modification of RNA by mRNA guanylyltransferase and mRNA (guanine-7-)methyltransferase from vaccinia virions.

A purified enzyme system isolated from vaccinia virus cores has been shown to modify the 5' termini of viral mRNA and synthetic poly(A) and poly(G) to form the structures m7G(5')pppA- and m7G(5')pppG-. The enzyme system has both guanylyltransferase and methyltransferase activities. The GTP:mRNA guanylyltransferase activity incorporates GMP into the 5' terminus via a 5'-5' triphosphate bond. The properties of this reaction are: (a) of the four nucleoside triphosphates only GTP is a donor, (b) mRNA with two phosphates at the 5' terminus is an acceptor while RNA with a single 5'-terminal phosphate is not, (c) Mg2+ is required, (d) the pH optimum is 7.8, (e) PP1 is a strong inhibitor, and (f) the reverse reaction, namely the formation of GTP from PP1 and RNA containing the 5'-terminal structure G(5')pppN-, readily occurs. The S-adenosylmethionine:mRNA(guanine-7-)methyltransferase activity catalyzes the methylation of the 5'-terminal guanosine. This reaction exhibits the following characteristics: (a) mRNA with the 5'-terminal sequences G(5')pppA- and G(5')pppG- are acceptors, (b) only position 7 of the terminal guanosine is methylated; internal or conventional 5'-terminal guanosine residues are not methylated, (c) the reaction is not dependent upon GTP or divalent cations, (d) optimal activity is observed in a broad pH range around neutrality, (e) the reaction is inhibited by S-adenosylhomocysteine. Both the guanylyltransferase and methyltransferase reactions exhibit bisubstrate kinetics and proceed via a sequential mechanism. The reactions may be summarized: (see article).

Cations, Divalent↗