Biogenesis and roles of tRNA queuosine modification and its glycosylated derivatives in human health and diseases.

Various types of post-transcriptional modifications contribute to physiological functions by regulating the abundance and function of RNAs. In particular, tRNAs have the widest variety and largest number of modifications, with crucial roles in protein synthesis. Queuosine (Q) is a characteristic tRNA modification with a 7-deazaguanosine core structure bearing a bulky side chain with a cyclopentene group.

Near-identical macromolecules spontaneously partition into concentric circles.

Although separation is entropically unfavourable, it is often essential for our life. The separation of very similar macromolecules such as deoxyribonucleic acids (DNAs) and their single nucleotide variants is difficult but holds great advantage for the progress of life science. Here we report that a particular liquid-liquid phase separation (LLPS) at a solid-liquid interface led to the partitioning of DNAs with nearly identical structures.

Toxic small alarmone synthetase FaRel2 inhibits translation by pyrophosphorylating tRNA and tRNA.

Translation-targeting toxic small alarmone synthetases (toxSAS) are effectors of bacterial toxin-antitoxin systems that pyrophosphorylate the 3'-CCA end of transfer RNA (tRNA) to prevent aminoacylation. toxSAS are implicated in antiphage immunity: Phage detection triggers the toxSAS activity to shut down viral production. We show that the toxSAS FaRel2 inspects the tRNA acceptor stem to specifically select tRNA and tRNA.

Cap-specific mAm modification: A transcriptional anti-terminator by sequestering PCF11 with implications for neuroblastoma therapy.

In this issue of Molecular Cell, An et al. reports a novel function of cap-specific mAm modification acting as an anti-terminator for premature RNA polymerase II transcription by sequestering a transcriptional terminator PCF11. This study provides new insights into RNA modifications in transcriptional control and cancer treatment.

Altered genomic methylation promotes Staphylococcus aureus persistence in hospital environment.

Staphylococcus aureus can cause outbreaks and becomes multi-drug resistant through gene mutations and acquiring resistance genes. However, why S. aureus easily adapts to hospital environments, promoting resistance and recurrent infections, remains unknown.

A tRNA modification with aminovaleramide facilitates AUA decoding in protein synthesis.

Modified tRNA anticodons are critical for proper mRNA translation during protein synthesis. It is generally thought that almost all bacterial tRNAs use a modified cytidine-lysidine (L)-at the first position (34) of the anticodon to decipher the AUA codon as isoleucine (Ile). Here we report that tRNAs from plant organelles and a subset of bacteria contain a new cytidine derivative, designated 2-aminovaleramididine (avaC).

Toxic Small Alarmone Synthetase FaRel2 inhibits translation by pyrophosphorylating tRNA and tRNA.

Translation-targeting toxic Small Alarmone Synthetases (toxSAS) are effectors of bacterial Toxin-Antitoxin systems that pyrophosphorylate the 3'-CCA end of tRNA to prevent aminoacylation. toxSAS are implicated in antiphage immunity: phage detection triggers the toxSAS activity to shut down viral production. We show that the toxSAS FaRel2 inspects the tRNA acceptor stem to specifically select tRNA and tRNA.

Functional redundancy of ubiquitin-like sulfur-carrier proteins facilitates flexible, efficient sulfur utilization in the primordial archaeon .

Ubiquitin-like proteins (Ubls) in eukaryotes and bacteria mediate sulfur transfer for the biosynthesis of sulfur-containing biomolecules and form conjugates with specific protein targets to regulate their functions. Here, we investigated the functions and physiological importance of Ubls in a hyperthermophilic archaeon by constructing a series of deletion mutants. We found that the Ubls (TK1065, TK1093, and TK2118) in are conjugated to their specific target proteins, and all three are involved in varying degrees in the biosynthesis of sulfur-containing biomolecules such as tungsten cofactor (Wco) and tRNA thiouridines.

Structural insights into the decoding capability of isoleucine tRNAs with lysidine and agmatidine.

The anticodon modifications of transfer RNAs (tRNAs) finetune the codon recognition on the ribosome for accurate translation. Bacteria and archaea utilize the modified cytidines, lysidine (L) and agmatidine (agmC), respectively, in the anticodon of tRNA to decipher AUA codon. L and agmC contain long side chains with polar termini, but their functions remain elusive.

Substrate specificity of Mycobacterium tuberculosis tRNA terminal nucleotidyltransferase toxin MenT3.

Mycobacterium tuberculosis transfer RNA (tRNA) terminal nucleotidyltransferase toxin, MenT3, incorporates nucleotides at the 3'-CCA end of tRNAs, blocking their aminoacylation and inhibiting protein synthesis. Here, we show that MenT3 most effectively adds CMPs to the 3'-CCA end of tRNA. The crystal structure of MenT3 in complex with CTP reveals a CTP-specific nucleotide-binding pocket.

An anticodon-sensing T-boxzyme generates the elongator nonproteinogenic aminoacyl-tRNA in situ of a custom-made translation system for incorporation.

In the hypothetical RNA world, ribozymes could have acted as modern aminoacyl-tRNA synthetases (ARSs) to charge tRNAs, thus giving rise to the peptide synthesis along with the evolution of a primitive translation apparatus. We previously reported a T-boxzyme, Tx2.1, which selectively charges initiator tRNA with N-biotinyl-phenylalanine (BioPhe) in situ in a Flexible In-vitro Translation (FIT) system to produce BioPhe-initiating peptides.

Transfer RNA modifications and cellular thermotolerance.

RNA molecules are modified post-transcriptionally to acquire their diverse functions. Transfer RNA (tRNA) has the widest variety and largest numbers of RNA modifications. tRNA modifications are pivotal for decoding the genetic code and stabilizing the tertiary structure of tRNA molecules.

Efficacy of Naldemedine on Intestinal Hypomotility and Adhesions in Rodent Models of Postoperative Ileus.

Postoperative ileus (POI) often decreases patients' QOL because of prolonged hospitalization and readmission. Alvimopan, a peripheral μ-opioid receptor antagonist, is currently the only therapeutic drug for POI. The aim of this study was to examine the efficacy of naldemedine (a peripheral μ-opioid receptor antagonist with a non-competitive pharmacological profile different from that of alvimopan) on postoperative intestinal hypomotility and adhesion in rodent models, and compare it with the effects of alvimopan.

Mitochondrial haplotype mutation alleviates respiratory defect of MELAS by restoring taurine modification in tRNA with 3243A > G mutation.

The 3243A > G in mtDNA is a representative mutation in mitochondrial diseases. Mitochondrial protein synthesis is impaired due to decoding disorder caused by severe reduction of 5-taurinomethyluridine (τm5U) modification of the mutant mt-tRNALeu(UUR) bearing 3243A > G mutation. The 3243A > G heteroplasmy in peripheral blood reportedly decreases exponentially with age.