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Unorthodox Mechanisms to Initiate Translation Open Novel Paths for Gene Expression.
Hernández, G, García, A, Sonenberg, N, Lasko, P
Journal of molecular biology. 2020;(24):166702
Abstract
Translation in eukaryotes is dependent on the activity of translation initiation factor (eIF) 4G family of proteins, a scaffold protein that, during the initiation step, coordinates the activity of other eIFs to recruit the 40S ribosomal subunit to the mRNA. Three decades of research on protein synthesis and its regulation has provided a wealth of evidence supporting the crucial role of cap-dependent translation initiation, which involves eIF4G. However, the recent discovery of a surprising variety of alternative mechanisms to initiate translation in the absence of eIF4G has stirred the orthodox view of how protein synthesis is performed. These mechanisms involve novel interactions among known eIFs, or between known eIFs and other proteins not previously linked to translation. Thus, a new picture is emerging in which the unorthodox translation initiation complexes contribute to the diversity of mechanisms that regulate gene expression in eukaryotes.
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2.
Epitranscriptomics in the Heart: a Focus on m6A.
Longenecker, JZ, Gilbert, CJ, Golubeva, VA, Martens, CR, Accornero, F
Current heart failure reports. 2020;(5):205-212
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PURPOSE OF REVIEW Post-transcriptional modifications are key regulators of gene expression that allow the cell to respond to environmental stimuli. The most abundant internal mRNA modification is N6-methyladenosine (m6A), which has been shown to be involved in the regulation of RNA splicing, localization, translation, and decay. It has also been implicated in a wide range of diseases, and here, we review recent evidence of m6A's involvement in cardiac pathologies and processes. RECENT FINDINGS Studies have primarily relied on gain and loss of function models for the enzymes responsible for adding and removing the m6A modification. Results have revealed a multifaceted role for m6A in the heart's response to myocardial infarction, pressure overload, and ischemia/reperfusion injuries. Genome-wide analyses of mRNAs that are differentially methylated during cardiac stress have highlighted the importance of m6A in regulating the translation of specific categories of transcripts implicated in pathways such as calcium handling, cell growth, autophagy, and adrenergic signaling in cardiomyocytes. Regulation of gene expression by m6A is critical for cardiomyocyte homeostasis and stress responses, suggesting a key role for this modification in cardiac pathophysiology.
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In Vitro Selection of Peptides and Proteins-Advantages of mRNA Display.
Newton, MS, Cabezas-Perusse, Y, Tong, CL, Seelig, B
ACS synthetic biology. 2020;(2):181-190
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mRNA display is a robust in vitro selection technique that allows the selection of peptides and proteins with desired functions from libraries of trillions of variants. mRNA display relies upon a covalent linkage between a protein and its encoding mRNA molecule; the power of the technique stems from the stability of this link, and the large degree of control over experimental conditions afforded to the researcher. This article describes the major advantages that make mRNA display the method of choice among comparable in vivo and in vitro methods, including cell-surface display, phage display, and ribosomal display. We also describe innovative techniques that harness mRNA display for directed evolution, protein engineering, and drug discovery.
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Molecular Mechanisms of pre-mRNA Splicing through Structural Biology of the Spliceosome.
Yan, C, Wan, R, Shi, Y
Cold Spring Harbor perspectives in biology. 2019;(1)
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Precursor messenger RNA (pre-mRNA) splicing is executed by the spliceosome. In the past 3 years, cryoelectron microscopy (cryo-EM) structures have been elucidated for a majority of the yeast spliceosomal complexes and for a few human spliceosomes. During the splicing reaction, the dynamic spliceosome has an immobile core of about 20 protein and RNA components, which are organized around a conserved splicing active site. The divalent metal ions, coordinated by U6 small nuclear RNA (snRNA), catalyze the branching reaction and exon ligation. The spliceosome also contains a mobile but compositionally stable group of about 13 proteins and a portion of U2 snRNA, which facilitate substrate delivery into the splicing active site. The spliceosomal transitions are driven by the RNA-dependent ATPase/helicases, resulting in the recruitment and dissociation of specific splicing factors that enable the reaction. In summary, the spliceosome is a protein-directed metalloribozyme.
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Messenger RNA therapy for rare genetic metabolic diseases.
Berraondo, P, Martini, PGV, Avila, MA, Fontanellas, A
Gut. 2019;(7):1323-1330
Abstract
Decades of intense research in molecular biology and biochemistry are fructifying in the emergence of therapeutic messenger RNAs (mRNA) as a new class of drugs. Synthetic mRNAs can be sequence optimised to improve translatability into proteins, as well as chemically modified to reduce immunogenicity and increase chemical stability using naturally occurring uridine modifications. These structural improvements, together with the development of safe and efficient vehicles that preserve mRNA integrity in circulation and allow targeted intracellular delivery, have paved the way for mRNA-based therapeutics. Indeed, mRNAs formulated into biodegradable lipid nanoparticles are currently being tested in preclinical and clinical studies for multiple diseases including cancer immunotherapy and vaccination for infectious diseases. An emerging application of mRNAs is the supplementation of proteins that are not expressed or are not functional in a regulated and tissue-specific manner. This so-called 'protein replacement therapy' could represent a solution for genetic metabolic diseases currently lacking effective treatments. Here we summarise this new class of drugs and discuss the preclinical evidence supporting the potential of liver-mediated mRNA therapy for three rare genetic conditions: methylmalonic acidaemia, acute intermittent porphyria and ornithine transcarbamylase deficiency.
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Nuclear mRNA Surveillance Mechanisms: Function and Links to Human Disease.
Singh, P, Saha, U, Paira, S, Das, B
Journal of molecular biology. 2018;(14):1993-2013
Abstract
Production of export-competent mRNAs involves transcription and a series of dynamic processing and modification events of pre-messenger RNAs in the nucleus. Mutations in the genes encoding the transcription and mRNP processing machinery and the complexities involved in the biogenesis events lead to the formation of aberrant messages. These faulty transcripts are promptly eliminated by the nuclear RNA exosome and its cofactors to safeguard the cells and organisms from genetic catastrophe. Mutations in the components of the core nuclear exosome and its cofactors lead to the tissue-specific dysfunction of exosomal activities, which are linked to diverse human diseases and disorders. In this article, we examine the structure and function of both the yeast and human RNA exosome complex and its cofactors, discuss the nature of the various altered amino acid residues implicated in these diseases with the speculative mechanisms of the mutation-induced disorders and project the frontier and prospective avenues of the future research in this field.
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[Intersubunit Mobility of the Ribosome].
Finkelstein, AV, Razin, SV, Spirin, AS
Molekuliarnaia biologiia. 2018;(6):921-934
Abstract
Ribosomes are ribonucleoprotein nanoparticles synthesizing all proteins in living cells. The function of the ribosome is to translate the genetic information encoded in a nucleotide sequence of mRNA into the amino acid sequence of a protein. Each translation step (occurring after the codon-dependent binding of the aminoacyl-tRNA with the ribosome and mRNA) includes (i) the transpeptidation reaction and (ii) the translocation that unidirectionally drives the mRNA chain and mRNA-bound tRNA molecules through the ribosomal intersubunit space; the latter process is driven by the free energy of the chemical reaction of transpeptidation. Thus, the translating ribosome can be considered a conveying protein-synthesizing molecular machine. In this review we analyze the role of ribosomal intersubunit mobility in the process of translocation.
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The special existences: nanoRNA and nanoRNase.
Liao, H, Liu, M, Guo, X
Microbiological research. 2018;:134-139
Abstract
To adapt to a wide range of nutritional and environmental changes, cells must adjust their gene expression profiles. This process is completed by the frequent transcription and rapid degradation of mRNA. mRNA decay is initiated by a series of endo- and exoribonucleases. These enzymes leave behind 2- to 5-nt-long oligoribonucleotides termed "nanoRNAs" that are degraded by specific nanoRNases; the degradation of nanoRNA is essential because nanoRNA can mediate the priming of transcription initiation that is harmful for the cell via an unknown mechanism. Identified nanoRNases include Orn in E. coli, NrnA and NrnB in B. subtilis, and NrnC in Bartonella. Even though these nanoRNases can degrade nanoRNA specifically into mononucleotides, the biochemical features, structural features and functional mechanisms of these enzymes are different. Sequence analysis has identified homologs of these nanoRNases in different bacteria, including Gammaproteobacteria, Betaproteobacteria, Alphaproteobacteria, Firmicutes and Cyanobacteria. However, there are several bacteria, such as those belonging to the class Thermolithobacteria, that do not have homologs of these nanoRNases. In this paper, the source of nanoRNA, the features of different kinds of nanoRNases and the distribution of these enzymes in prokaryotes are described in detail.
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[Functional implications of single nucleotide polymorphisms (SNPs) in protein-coding and non-coding RNA genes in multifactorial diseases].
Ramírez-Bello, J, Jiménez-Morales, M
Gaceta medica de Mexico. 2017;(2):238-250
Abstract
Single nucleotide polymorphisms (SNPs) represent the most common type of variation in the human genome. The SNPs located in protein-coding and non-coding RNA genes are classified as neutral and functional. The neutral have no effect, while the functional affect different biological processes and continually confer risk for multifactorial diseases. Functional SNPs found in the promoters of protein-coding and non-coding RNA genes (microRNAs: miRNAs) termed regulatory SNP (rSNPs) and miRNAs rSNPs (miR-rSNPs), respectively, affect the gene expression. Functional SNPs located on the structure of the precursor mRNAs (exons and introns), mature mRNA (5´ untranslated region [UTR], coding sequence, and 3´ UTR), and primary, precursor, and mature miRNAs are termed structural RNA SNPs (srSNPs) and miR-srSNPs, respectively. The srSNPs affect the splicing (and alternative splicing), srSNPs affect the splicing (and alternative splicing), the translation, stability, amino acid sequence, structure, and function of proteins and interaction between mRNA/miRNAs. Finally, the miR-srSNPs affect the structure, processing and interaction between miRNAs/mRNAs. Functional characterization of potentially harmful risk alleles of the SNPs located in protein-coding and non-coding RNA genes have contributed to an understanding of their functions in the complex diseases. The objective of this review is update the reader on the functional role of the SNPs located in protein-coding and non-coding RNA genes and their relationship with multifactorial diseases.
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10.
Decoding sORF translation - from small proteins to gene regulation.
Cabrera-Quio, LE, Herberg, S, Pauli, A
RNA biology. 2016;(11):1051-1059
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Translation is best known as the fundamental mechanism by which the ribosome converts a sequence of nucleotides into a string of amino acids. Extensive research over many years has elucidated the key principles of translation, and the majority of translated regions were thought to be known. The recent discovery of wide-spread translation outside of annotated protein-coding open reading frames (ORFs) came therefore as a surprise, raising the intriguing possibility that these newly discovered translated regions might have unrecognized protein-coding or gene-regulatory functions. Here, we highlight recent findings that provide evidence that some of these newly discovered translated short ORFs (sORFs) encode functional, previously missed small proteins, while others have regulatory roles. Based on known examples we will also speculate about putative additional roles and the potentially much wider impact that these translated regions might have on cellular homeostasis and gene regulation.