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Proceedings of the National Academy of... Oct 2023Precursor tRNAs are transcribed with flanking and intervening sequences known to be processed by specific ribonucleases. Here, we show that transcription complexes of...
Precursor tRNAs are transcribed with flanking and intervening sequences known to be processed by specific ribonucleases. Here, we show that transcription complexes of RNA polymerase III assembled on tRNA genes comprise RNase P that cleaves precursor tRNA and subsequently degrades the excised 5' leader. Degradation is based on a 3'-5' exoribonucleolytic activity carried out by the protein subunit Rpp14, as determined by biochemical and reverse genetic analyses. Neither reconstituted nor purified RNase P displays this magnesium ion-dependent, processive exoribonucleolytic activity. Markedly, knockdown of Rpp14 by RNA interference leads to a wide-ranging inhibition of cleavage of flanking and intervening sequences of various precursor tRNAs in extracts and cells. This study reveals that RNase P controls tRNA splicing complex and RNase Z for ordered maturation of nascent precursor tRNAs by transcription complexes.
Topics: Humans; Ribonuclease P; RNA Precursors; Endoribonucleases; RNA, Transfer; Ribonucleases; RNA Splicing
PubMed: 37831743
DOI: 10.1073/pnas.2307185120 -
Nature Oct 2018Quaternary amino acids, in which the α-carbon that bears the amino and carboxyl groups also carries two carbon substituents, have an important role as modifiers of...
Quaternary amino acids, in which the α-carbon that bears the amino and carboxyl groups also carries two carbon substituents, have an important role as modifiers of peptide conformation and bioactivity and as precursors of medicinally important compounds. In contrast to enantioselective alkylation at this α-carbon, for which there are several methods, general enantioselective introduction of an aryl substituent at the α-carbon is synthetically challenging. Nonetheless, the resultant α-aryl amino acids and their derivatives are valuable precursors to bioactive molecules. Here we describe the synthesis of quaternary α-aryl amino acids from enantiopure amino acid precursors by α-arylation without loss of stereochemical integrity. Our approach relies on the temporary formation of a second stereogenic centre in an N'-arylurea adduct of an imidazolidinone derivative of the precursor amino acid, and uses readily available enantiopure amino acids both as a precursor and as a source of asymmetry. It avoids the use of valuable transition metals, and enables arylation with electron-rich, electron-poor and heterocyclic substituents. Either enantiomer of the product can be formed from a single amino acid precursor. The method is practical and scalable, and provides the opportunity to produce α-arylated quaternary amino acids in multi-gram quantities.
Topics: Alkylation; Amino Acids; Chemistry Techniques, Synthetic; Imidazolidines; Models, Chemical; Stereoisomerism
PubMed: 30283103
DOI: 10.1038/s41586-018-0553-9 -
Advanced Materials (Deerfield Beach,... Jun 2023Materials synthesis via liquid-like mineral precursors has been studied since their discovery almost 25 years ago, because their properties offer several advantages, for...
Materials synthesis via liquid-like mineral precursors has been studied since their discovery almost 25 years ago, because their properties offer several advantages, for example, the ability to infiltrate small pores, the production of non-equilibrium crystal morphologies or mimicking textures from biominerals, resulting in a vast range of possible applications. However, the potential of liquid-like precursors has never been fully tapped, and they have received limited attention in the materials chemistry community, largely due to the lack of efficient and scalable synthesis protocols. Herein, the "scalable controlled synthesis and utilization of liquid-like precursors for technological applications" (SCULPT) method is presented, allowing the isolation of the precursor phase on a gram scale, and its advantage in the synthesis of crystalline calcium carbonate materials and respective applications is demonstrated. The effects of different organic and inorganic additives, such as magnesium ions and concrete superplasticizers, on the stability of the precursor are investigated and allow optimizing the process for specific demands. The presented method is easily scalable and therefore allows synthesizing and utilizing the precursor on large scales. Thus, it can be employed for mineral formation during restoration and conservation applications but can also open up pathways toward calcium carbonate-based, CO -neutral cements.
PubMed: 36971032
DOI: 10.1002/adma.202300702 -
Current Opinion in Hematology Jul 2017Loss of IKAROS in committed B cell precursors causes a block in differentiation while at the same time augments aberrant cellular properties, such as bone marrow stromal... (Review)
Review
PURPOSE OF REVIEW
Loss of IKAROS in committed B cell precursors causes a block in differentiation while at the same time augments aberrant cellular properties, such as bone marrow stromal adhesion, self-renewal and resistance to glucocorticoid-mediated cell death. B cell acute lymphoblastic leukaemias originating from these early stages of B cell differentiation and associated with IKAROS mutations share a high-risk cellular phenotype suggesting that deregulation of IKAROS-based mechanisms cause a highly malignant disease process.
RECENT STUDIES
Recent studies show that IKAROS is critical for the activity of super-enhancers at genes required for pre-B cell receptor (BCR) signalling and differentiation, working either downstream of or in parallel with B cell master regulators such as EBF1 and PAX5. IKAROS also directly represses a cryptic regulatory network of transcription factors prevalent in mesenchymal and epithelial precursors that includes YAP1, TEAD1/2, LHX2 and LMO2, and their targets, which are not normally expressed in lymphocytes. IKAROS prevents not only expression of these 'extra-lineage' transcription factors but also their cooperation with endogenous B cell master regulators, such as EBF1 and PAX5, leading to the formation of a de novo for lymphocytes super-enhancer network. IKAROS coordinates with the Polycomb repression complex (PRC2) to provide stable repression of associated genes during B cell development. However, induction of regulatory factors normally repressed by IKAROS starts a feed-forward loop that activates de-novo enhancers and elevates them to super-enhancer status, thereby diminishing PRC2 repression and awakening aberrant epithelial-like cell properties in B cell precursors.
SUMMARY
Insight into IKAROS-based transcriptional circuits not only sets new paradigms for cell differentiation but also provides new approaches for classifying and treating high-risk human B-ALL that originates from these early stages of B cell differentiation.
Topics: Animals; B-Lymphocytes; Cell Differentiation; Cell Proliferation; Cell Self Renewal; Cell Transformation, Neoplastic; Enhancer Elements, Genetic; Gene Expression Regulation; Gene Regulatory Networks; Humans; Ikaros Transcription Factor; Polycomb-Group Proteins; Precursor Cells, B-Lymphoid; Protein Binding; Transcription, Genetic
PubMed: 28463873
DOI: 10.1097/MOH.0000000000000352 -
Nanomaterials (Basel, Switzerland) Jun 2023The fabrication of thin-film electrodes, which contain metal nanoparticles and nanostructures for applications in electrochemical sensing as well as energy conversion... (Review)
Review
The fabrication of thin-film electrodes, which contain metal nanoparticles and nanostructures for applications in electrochemical sensing as well as energy conversion and storage, is often based on multi-step procedures that include two main passages: (i) the synthesis and purification of nanomaterials and (ii) the fabrication of thin films by coating electrode supports with these nanomaterials. The patterning and miniaturization of thin film electrodes generally require masks or advanced patterning instrumentation. In recent years, various approaches have been presented to integrate the spatially resolved deposition of metal precursor solutions and the rapid conversion of the precursors into metal nanoparticles. To achieve the latter, high intensity light irradiation has, in particular, become suitable as it enables the photochemical, photocatalytical, and photothermal conversion of the precursors during or slightly after the precursor deposition. The conversion of the metal precursors directly on the target substrates can make the use of capping and stabilizing agents obsolete. This review focuses on hybrid platforms that comprise digital metal precursor ink printing and high intensity light irradiation for inducing metal precursor conversions into patterned metal and alloy nanoparticles. The combination of the two methods has recently been named Print-Light-Synthesis by a group of collaborators and is characterized by its sustainability in terms of low material consumption, low material waste, and reduced synthesis steps. It provides high control of precursor loading and light irradiation, both affecting and improving the fabrication of thin film electrodes.
PubMed: 37446431
DOI: 10.3390/nano13131915 -
Bioscience Reports Mar 2023RNA is a fundamental biomolecule that has many purposes within cells. Due to its single-stranded and flexible nature, RNA naturally folds into complex and dynamic... (Review)
Review
RNA is a fundamental biomolecule that has many purposes within cells. Due to its single-stranded and flexible nature, RNA naturally folds into complex and dynamic structures. Recent technological and computational advances have produced an explosion of RNA structural data. Many RNA structures have regulatory and functional properties. Studying the structure of nascent RNAs is particularly challenging due to their low abundance and long length, but their structures are important because they can influence RNA processing. Precursor RNA processing is a nexus of pathways that determines mature isoform composition and that controls gene expression. In this review, we examine what is known about human nascent RNA structure and the influence of RNA structure on processing of precursor RNAs. These known structures provide examples of how other nascent RNAs may be structured and show how novel RNA structures may influence RNA processing including splicing and polyadenylation. RNA structures can be targeted therapeutically to treat disease.
Topics: Humans; RNA Precursors; RNA Splicing; RNA; Polyadenylation; Gene Expression
PubMed: 36689327
DOI: 10.1042/BSR20220149 -
Molecules (Basel, Switzerland) Mar 2024During the life activities of microorganisms, a variety of secondary metabolites are produced, including antimicrobials and antitumor drugs, which are widely used in... (Review)
Review
During the life activities of microorganisms, a variety of secondary metabolites are produced, including antimicrobials and antitumor drugs, which are widely used in clinical practice. In addition to exploring new antibiotics, this makes it one of the research priorities of to effectively increase the yield of antibiotics in production strains by various means. Most antibiotic-producing strains have a variety of functional regulatory factors that regulate their growth, development, and secondary metabolite biosynthesis processes. Through the study of precursor substances in antibiotic biosynthesis, researchers have revealed the precursor biosynthesis process and the mechanism by which precursor synthesis regulators affect the biosynthesis of secondary metabolites, which can be used to obtain engineered strains with high antibiotic production. This paper summarizes the supply of antibiotic biosynthesis precursors and the progress of research on the role of regulators in the process of precursors in biosynthesis. This lays the foundation for the establishment of effective breeding methods to improve antibiotic yields through the manipulation of precursor synthesis genes and related regulators.
Topics: Anti-Bacterial Agents; Actinobacteria; Actinomyces; Secondary Metabolism
PubMed: 38474644
DOI: 10.3390/molecules29051132 -
Substance Abuse and Rehabilitation 2022Recreational gamma-hydroxybutyrate (GHB) use, although less common than other substance use, is increasingly recognised and is over-represented in emergency toxicology... (Review)
Review
Recreational gamma-hydroxybutyrate (GHB) use, although less common than other substance use, is increasingly recognised and is over-represented in emergency toxicology presentations. This narrative review summarizes GHB pharmacology, current patterns of use, potential harms and management of GHB toxicity and withdrawal. There is a complex interplay between GHB and GABA as GHB is both a prodrug and metabolite of GABA and GHB activates both GHB and GABA receptors. GHB is rapidly absorbed, with effects seen within minutes of ingestion. Metabolism is non-linear at higher doses. While GHB is listed as a controlled substance, its precursor's gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are easily available as both have industrial applications. National surveys indicate low rates of GHB use, with identification of high-risk populations in men who have sex with men and polysubstance users. GHB is one of the three drugs most commonly used in chemsex. GHB is often co-ingested with other interacting psychoactive substances. Acute toxicity is dose-dependent, and management is supportive care. Withdrawal management is generally with benzodiazepines with addition of baclofen for more severe withdrawal. Barbiturates may have a role. Titration and tapering of pharmaceutical GHB is commonly used in the Netherlands. Complicated withdrawal with delirium may require intensive care and treatment with intravenous sedation. There are high rates of relapse after withdrawal and medications for longer-term management are currently being investigated. Chronic use is associated with poorer mental, physical and sexual health, social dysfunction and poor work performance. Laboratory detection is complicated as GHB is an endogenous substance with a short half-life, and therefore not often routinely assayed in the clinical setting. Future research should focus on improving GHB detection and management of GHB withdrawal and dependence. Interventions specific for high-risk groups should be developed and assessed.
PubMed: 35173515
DOI: 10.2147/SAR.S315720 -
Genomics, Proteomics & Bioinformatics May 2024Ribonuclease P (RNase P) was first described in the 1970's as an endoribonuclease acting in the maturation of precursor transfer RNAs (tRNAs). More recent studies,... (Review)
Review
Ribonuclease P (RNase P) was first described in the 1970's as an endoribonuclease acting in the maturation of precursor transfer RNAs (tRNAs). More recent studies, however, have uncovered non-canonical roles for RNase P and its components. Here, we review the recent progress of its involvement in chromatin assembly, DNA damage response, and maintenance of genome stability with implications in tumorigenesis. The possibility of RNase P as a therapeutic target in cancer is also discussed.
Topics: Ribonuclease P; Humans; RNA, Transfer; Neoplasms; RNA Precursors; Genomic Instability; Animals; DNA Damage; RNA Processing, Post-Transcriptional; Chromatin Assembly and Disassembly
PubMed: 38862431
DOI: 10.1093/gpbjnl/qzae016 -
International Journal of Hematology Sep 2014The Ikaros family of DNA-binding proteins are critical regulators of lymphocyte differentiation. In multipotent, hematopoietic progenitors, Ikaros supports... (Review)
Review
The Ikaros family of DNA-binding proteins are critical regulators of lymphocyte differentiation. In multipotent, hematopoietic progenitors, Ikaros supports transcriptional priming of genes promoting lymphocyte differentiation. Ikaros targets the Nucleosome Remodeling Deacetylase (NuRD) complex to lymphoid lineage genes, thereby increasing chromatin accessibility and transcriptional priming. After lymphoid lineage specification, Ikaros expression is raised to levels characteristic of intermediate B cell and T cell precursors, which is necessary to support maturation and prevent leukemogenesis. Loss of Ikaros in T cell precursors allows the NuRD complex to repress lymphocyte genes and extends its targeting to genes that support growth and proliferation, causing their activation and triggering a cascade of events that leads to leukemogenesis. Loss of Ikaros in B cell precursors blocks differentiation and perpetuates stromal adhesion by enhancing integrin signaling. The combination of integrin and cytokine signaling in Ikaros-deficient pre-B cells promotes their survival and self-renewal. The stages of lymphocyte differentiation that are highly dependent on Ikaros are underscored by changes in Ikaros transcription, supported by a complex network of stage-specific regulatory networks that converge upon the Ikzf1 locus. It is increasingly apparent that understanding the regulatory networks that operate upstream and downstream of Ikaros is critical not only for our understanding of normal lymphopoiesis, but also in placing the right finger on the mechanisms that support hematopoietic malignancies in mouse and human.
Topics: Animals; Autoantigens; Cell Differentiation; Cell Lineage; Epigenesis, Genetic; Hematopoietic Stem Cells; Humans; Ikaros Transcription Factor; Lymphopoiesis; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Mice; Precursor Cells, B-Lymphoid; Precursor Cells, T-Lymphoid; Protein Isoforms; Signal Transduction
PubMed: 25085254
DOI: 10.1007/s12185-014-1644-5