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PubMed2026

tRNA m1A modification orchestrates STING translation in macrophages to enhance antitumor immunity and CAR-macrophage immunotherapy.

Tumor-associated macrophages (TAMs) play crucial roles in tumor progression. However, the mechanisms underlying the posttranscriptional regulation of TAMs remain largely unknown. Here, we demonstrated that Trmt61a, the "writer" enzyme of tRNA N1-methyladenosine (m1A) modification, is highly expressed in proinflammatory macrophages in tumor microenvironment. We generated conditional knockout (KO) mice for Trmt61a and observed that Trmt61a deletion in macrophages significantly promoted tumor growth. Mechanistically, we identified that m1A maintains the translation of STING, enhances STING-TBK1-IFN-β signaling in macrophages and therefore suppresses tumor cell growth. We further generated TRMT61A-overexpressing human iPSC-derived CAR-macrophage and demonstrated that human TRMT61A effectively promoted antitumor CAR-macrophage therapy in vivo. Collectively, our findings reveal a novel regulatory mechanism of tRNA m1A modification in macrophages, highlighting the antitumor therapeutic potential of targeting tRNA m1A modification in macrophages.

Animals↗

PubMed2025

MapID-based quantitative mapping of chemical modifications and expression of human transfer RNA.

Detection and quantification of tRNA chemical modifications are critical for understanding their regulatory functions in biology and diseases. However, tRNA-seq-based methods for modification mapping encountered challenges both experimentally (poor processivity of heavily modified tRNAs during reverse transcription or RT) and bioinformatically (frequent reads misalignment to highly similar tRNA genes). Here, we report "MapID-tRNA-seq" where we deployed an evolved reverse transcriptase (RT-1306) into tRNA-seq and developed "MapIDs" that reduce redundancy of the human tRNA genome and explicitly annotate genetic variances. RT-1306 generated robust mutations against m1A and m3C, and RT stops against multiple bulky roadblock modifications. MapID-assisted data processing enabled systematic exclusion of false-positive discoveries of modifications which arise from reads misalignment onto similar genes. We applied MapID-tRNA-seq into mapping m1A, m3C and expression levels of tRNAs in three mammary cell lines, which revealed cell-type dependent modification sites and potential translational regulation of the reduced mitochondrial activities in breast cancer.

Humans↗

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↗

PubMed2024

TGIRT-seq to profile tRNA-derived RNAs and associated RNA modifications.

RNA modifications are key regulators for RNA processes. tRNA-derived RNAs are small RNAs with size between 15 and 50 bases long that are processed from mature or precursor tRNAs. Despite their more recent discovery, tRNA-derived RNAs have been found to play regulatory roles in many cellular processes including gene silencing, protein synthesis, stress response, and transgenerational inheritance. Furthermore, tRNA-derived RNAs are highly abundant in bodily fluids, posing as potential biomarkers. A unique feature of tRNA-derived RNAs is that they are rich in RNA modifications. Many of the RNA modifications on tRNA-derived RNAs disrupt Watson-Crick base pairing and will thus stall reverse transcriptase, such as N1-methyladenosine (m1A), N1-methylguanosine (m1G) and N2, N2-dimethylguanosine (m22G). These RNA modifications add another layer of regulation onto tRNA-derived RNAs' functions and are of interests for future research. However, these RNA modifications could also lead to lower detection of modification-containing RNAs in genome-wide small RNA sequencing analysis due to reverse transcriptase stall. To circumvent this bias, TGIRT (Thermostable Group II Intron Reverse Transcriptase) has been used to readthrough RNA modifications inserting mismatches. These mismatch signatures can then be used to precisely map the modification sites at base resolution. Here we describe the step-by-step experimental protocol to start with purified RNAs from cells or tissues and use TGIRT to make small RNA sequencing library for Illumina sequencing to profile the abundance of tRNA-derived RNAs and the associated RNA modifications.

RNA, Transfer↗

PubMed2024

Abundant mRNA m1A modification in dinoflagellates: a new layer of gene regulation.

Dinoflagellates, a class of unicellular eukaryotic phytoplankton, exhibit minimal transcriptional regulation, representing a unique model for exploring gene expression. The biosynthesis, distribution, regulation, and function of mRNA N1-methyladenosine (m1A) remain controversial due to its limited presence in typical eukaryotic mRNA. This study provides a comprehensive map of m1A in dinoflagellate mRNA and shows that m1A, rather than N6-methyladenosine (m6A), is the most prevalent internal mRNA modification in various dinoflagellate species, with an asymmetric distribution along mature transcripts. In Amphidinium carterae, we identify 6549 m1A sites characterized by a non-tRNA T-loop-like sequence motif within the transcripts of 3196 genes, many of which are involved in regulating carbon and nitrogen metabolism. Enriched within 3'UTRs, dinoflagellate mRNA m1A levels negatively correlate with translation efficiency. Nitrogen depletion further decreases mRNA m1A levels. Our data suggest that distinctive patterns of m1A modification might influence the expression of metabolism-related genes through translational control.

Dinoflagellida↗

PubMed1979

Nucleotide sequence of starfish initiator tRNA.

The nucleotide sequence of starfish ovary initiator tRNA was determined to be pA-G-C-A-G-A-G-U-m1G-m2G-C-G-C-A-G-U-G-G-A-A-G-C-G-U-G-C-U-G-G-G-C-C-C-A-U-t6A-A-C-C-C-A-G-A-G-m7G-D-m5C-C-G-A-G-G-A-psi-C-G-m1A-A-A-C-C-U-C-G-C-U-C-U-G-C-U-A-C-C-AOH. The sequence was determined by a combination of the two different post-labeling techniques. Two-dimensional cellulose thin-layer chromatography was adopted for analysis of 5'-terminal nucleotides of tRNA fragments produced by formamide treatment. The nucleotide sequence of starfish initiator tRNA is very similar to that of mammalian cytoplasmic initiator tRNAs, but has seven different nucleotide residues and two modifications: residue 55 is psi instead of U, and residue 26 is unmodified G instead of m2G.

Amino Acyl-tRNA Synthetases↗