Human BCDIN3D Is a Cytoplasmic tRNAHis-Specific 5′-Monophosphate Methyltransferase

Bicoid interacting 3 domain containing RNA methyltransferase (BCDIN3D) is a member of the Bin3 methyltransferase family and is evolutionary conserved from worm to human. BCDIN3D is overexpressed in breast cancer, which is associated with poor prognosis of breast cancers. However, the biological functions and properties of BCDIN3D have been enigmatic. Recent studies have revealed that human BCDIN3D monomethylates 5′-monophsosphate of cytoplasmic tRNAHisin vivo and in vitro. BCDIN3D recognizes the unique and exceptional structural features of cytoplasmic tRNAHis and discriminates tRNAHis from other cytoplasmic tRNA species. Thus, BCDIN3D is a tRNAHis-specific 5′-monophosphate methyltransferase. Methylation of the 5′-phosphate group of tRNAHis does not significantly affect tRNAHis aminoacylation by histidyl-tRNA synthetase in vitro nor the steady state level or stability of tRNAHisin vivo. Hence, methylation of the 5′-phosphate group of tRNAHis by BCDIN3D or tRNAHis itself may be involved in certain unknown biological processes, beyond protein synthesis. This review discusses recent reports on BCDIN3D and the possible association between 5′-phosphate monomethylation of tRNAHis and the tumorigenic phenotype of breast cancer

Function and Regulation of Human Terminal Uridylyltransferases

RNA uridylylation plays a pivotal role in the biogenesis and metabolism of functional RNAs, and regulates cellular gene expression. RNA uridylylation is catalyzed by a subset of proteins from the non-canonical terminal nucleotidyltransferase family. In human, three proteins (TUT1, TUT4, and TUT7) have been shown to exhibit template-independent uridylylation activity at 3′-end of specific RNAs. TUT1 catalyzes oligo-uridylylation of U6 small nuclear (sn) RNA, which catalyzes mRNA splicing. Oligo-uridylylation of U6 snRNA is required for U6 snRNA maturation, U4/U6-di-snRNP formation, and U6 snRNA recycling during mRNA splicing. TUT4 and TUT7 catalyze mono- or oligo-uridylylation of precursor let-7 (pre–let-7). Let-7 RNA is broadly expressed in somatic cells and regulates cellular proliferation and differentiation. Mono-uridylylation of pre–let-7 by TUT4/7 promotes subsequent Dicer processing to up-regulate let-7 biogenesis. Oligo-uridylylation of pre–let-7 by TUT4/7 is dependent on an RNA-binding protein, Lin28. Oligo-uridylylated pre–let-7 is less responsive to processing by Dicer and degraded by an exonuclease DIS3L2. As a result, let-7 expression is repressed. Uridylylation of pre–let-7 depends on the context of the 3′-region of pre–let-7 and cell type. In this review, we focus on the 3′ uridylylation of U6 snRNA and pre-let-7, and describe the current understanding of mechanism of activity and regulation of human TUT1 and TUT4/7, based on their crystal structures that have been recently solved

Increased Level of Pericardial Insulin-Like Growth Factor-1 in Patients With Left Ventricular Dysfunction and Advanced Heart Failure

ObjectivesTo test the hypothesis that the cardiac insulin-like growth factor-1 (IGF-1) system is up-regulated in the failing heart, we measured the pericardial (cardiac) and plasma (circulating) IGF-1 levels in coronary artery disease patients.BackgroundLocal IGF-1 systems are regulated differently from the systemic IGF-1 system. The cardiac IGF-1 system is up-regulated by the increased left ventricular (LV) wall stress. However, it remains unknown how this system is affected in LV dysfunction and heart failure.MethodsWe measured the plasma and pericardial fluid levels of IGF-1 and brain natriuretic peptide (BNP) in 87 coronary artery disease patients undergoing cardiac surgery, and examined their relationships with LV function and heart failure severity. The expressions of IGF-1 and IGF-1 receptor proteins were examined in endomyocardial biopsies obtained from other patients with normal or impaired LV function.ResultsThe pericardial IGF-1 and BNP levels were positively correlated with the plasma BNP level (both p < 0.001). The pericardial IGF-1 level was increased in heart failure patients, whereas the plasma IGF-1 level was rather decreased. The pericardial IGF-1 level was inversely correlated with the LV ejection fraction (p < 0.001), whereas the plasma IGF-1 level was not. Positive immunostaining for IGF-1 and IGF-1 receptor proteins was enhanced in myocardial biopsies from failing hearts compared with those from nonfailing hearts.ConclusionsThe pericardial IGF-1 level was increased in patients with LV dysfunction and heart failure, whereas the plasma IGF-1 level was decreased. These results may indicate that up-regulation of the cardiac IGF-1 system serves as a compensatory mechanism for LV dysfunction

A possible link between specific transfer RNA methylation and tumorigenic phenotype of breast cancer: DOI: 10.14800/rd.1530

The human RNA methyltransferase BCDIN3D is overexpressed in breast cancer cells and involved in cellular invasion and poor prognosis of breast cancer. Several years ago, BCDIN3D was reported to dimethylate the 5'-monophosphate of specific precursor miRNAs (pre-miRNAs), such as the tumor suppressor miR145. Dimethylation of the 5'-monophosphate of the pre-miRNA negatively regulates the subsequent processing by Dicer in vitro, and results in the downregulated expression of the mature form of the miRNA. The depletion of BCDIN3D also reportedly results in the suppression of the tumorigenic phenotype of breast cancer cells. Thus, these findings suggested that BCDIN3D promotes the cellular invasion of breast cancer cells, by downregulating the expression of tumor suppressor miRNAs via the dimethylation of the 5'-monophosphate of the corresponding pre-miRNAs. Recently, we found that cytoplasmic tRNAHis is actually the primary target of human BCDIN3D, rather than pre-miR145. BCDIN3D monomethylates the 5'-phosphate of cytoplasmic tRNAHis much more efficiently than that of pre-miRNA in vitro, and is responsible for the monomethylation of the 5'-phosphate of cytoplasmic tRNAHisin vivo. BCDIN3D recognizes the eight-nucleotide long extended acceptor helix with the G-1-A73 mis-pair at the top of the acceptor stem of tRNAHis, which are exceptional features among cytoplasmic tRNA species. These results not only reveal the primary target of BCDIN3D, which is overexpressed in breast cancer cells, but also highlight the possible involvement of the 5'-phosphomethylation of tRNA and/or tRNA in the tumorigenesis of breast cancer cells, beyond its established function in protein synthesis

Structures and Functions of Qβ Replicase: Translation Factors beyond Protein Synthesis

Qβ replicase is a unique RNA polymerase complex, comprising Qβ virus-encoded RNA-dependent RNA polymerase (the catalytic β-subunit) and three host-derived factors: translational elongation factor (EF) -Tu, EF-Ts and ribosomal protein S1. For almost fifty years, since the isolation of Qβ replicase, there have been several unsolved, important questions about the mechanism of RNA polymerization by Qβ replicase. Especially, the detailed functions of the host factors, EF-Tu, EF-Ts, and S1, in Qβ replicase, which are all essential in the Escherichia coli (E. coli) host for protein synthesis, had remained enigmatic, due to the absence of structural information about Qβ replicase. In the last five years, the crystal structures of the core Qβ replicase, consisting of the β-subunit, EF-Tu and Ts, and those of the core Qβ replicase representing RNA polymerization, have been reported. Recently, the structure of Qβ replicase comprising the β-subunit, EF-Tu, EF-Ts and the N-terminal half of S1, which is capable of initiating Qβ RNA replication, has also been reported. In this review, based on the structures of Qβ replicase, we describe our current understanding of the alternative functions of the host translational elongation factors and ribosomal protein S1 in Qβ replicase as replication factors, beyond their established functions in protein synthesis

Effects of ingestion of difructose anhydride III (DFA III) and the DFA III-assimilating bacterium Ruminococcus productus on rat intestine.

We have isolated a difructose anhydride III (DFA III)-assimilating bacterium, Ruminococcus productus AHU1760, from human. After an acclimation period of 1 week, male Sprague-Dawley rats (5 weeks old) were divided into four groups (control diet, R. productus diet, DFA III diet, and R. productus + DFA III diet; n=8) and fed the assigned test diets for 2 weeks. The viable count of administered R. productus was 4.9×107 CFU/d in R. productus-fed rats and 4.7×107 CFU/d in R. productus + DFA III-fed rats. Survival in cecal content of this strain was confirmed by randomly amplified polymorphic DNA. The ratio of secondary bile acids in feces in R. productus + DFA III-fed rats decreased the same as that in rats fed only DFA III. The viable count of lactobacilli and bifidobacteria, known as beneficial bacteria, increased more in R. productus + DFA III-fed rats than in control or R. productus-fed rats. A combination of R. productus and DFA III might improve the balance of intestinal microbiota to a healthier condition