-
International Journal of Molecular... Sep 2023In the last few decades, RNA-based drugs have emerged as a promising candidate in the treatment of various diseases. The introduction of messenger RNA (mRNA) as a... (Review)
Review
In the last few decades, RNA-based drugs have emerged as a promising candidate in the treatment of various diseases. The introduction of messenger RNA (mRNA) as a vaccine or therapeutic agent enables the production of almost any functional protein/peptide. The key to applying RNA therapy in clinical trials is developing safe and effective delivery systems. Exosomes and lipid nanoparticles (LNPs) have been exploited as promising vehicles for drug delivery. This review discusses the feasibility of exosomes and LNPs as vehicles for mRNA delivery. Cancer/testis antigens (CTAs) show restricted expression in normal tissues and widespread expression in cancer tissues. Many of these CTAs show expression in the sera of patients with cancers. These characteristics of CTAs make them excellent targets for cancer immunotherapy. This review summarizes the roles of CTAs in various life processes and current studies on mRNAs encoding CTAs. Clinical studies present the beneficial effects of mRNAs encoding CTAs in patients with cancers. This review highlight clinical studies employing mRNA-LNPs encoding CTAs.
Topics: Male; Humans; Antigens, Neoplasm; Testis; RNA; Neoplasms; RNA, Messenger
PubMed: 37834126
DOI: 10.3390/ijms241914679 -
Biochimica Et Biophysica Acta. Gene... Jun 2024RNA polymerase II (Pol II) is the multi-protein complex responsible for transcribing all protein-coding messenger RNA (mRNA). Most research on gene regulation is focused... (Review)
Review
RNA polymerase II (Pol II) is the multi-protein complex responsible for transcribing all protein-coding messenger RNA (mRNA). Most research on gene regulation is focused on the mechanisms controlling which genes are transcribed when, or on the mechanics of transcription. How global Pol II activity is determined receives comparatively less attention. Here, we follow the life of a Pol II molecule from 'assembly of the complex' to nuclear import, enzymatic activity, and degradation. We focus on how Pol II spends its time in the nucleus, and on the two-way relationship between Pol II abundance and activity in the context of homeostasis and global transcriptional changes.
Topics: RNA Polymerase II; Transcription, Genetic; Humans; Gene Expression Regulation; Cell Nucleus; RNA, Messenger; Active Transport, Cell Nucleus; Animals
PubMed: 38552781
DOI: 10.1016/j.bbagrm.2024.195024 -
Molecular Cell Dec 2023Reactive aldehydes are produced by normal cellular metabolism or after alcohol consumption, and they accumulate in human tissues if aldehyde clearance mechanisms are...
Reactive aldehydes are produced by normal cellular metabolism or after alcohol consumption, and they accumulate in human tissues if aldehyde clearance mechanisms are impaired. Their toxicity has been attributed to the damage they cause to genomic DNA and the subsequent inhibition of transcription and replication. However, whether interference with other cellular processes contributes to aldehyde toxicity has not been investigated. We demonstrate that formaldehyde induces RNA-protein crosslinks (RPCs) that stall the ribosome and inhibit translation in human cells. RPCs in the messenger RNA (mRNA) are recognized by the translating ribosomes, marked by atypical K6-linked ubiquitylation catalyzed by the RING-in-between-RING (RBR) E3 ligase RNF14, and subsequently resolved by the ubiquitin- and ATP-dependent unfoldase VCP. Our findings uncover an evolutionary conserved formaldehyde-induced stress response pathway that protects cells against RPC accumulation in the cytoplasm, and they suggest that RPCs contribute to the cellular and tissue toxicity of reactive aldehydes.
Topics: Humans; RNA; Ubiquitination; Ubiquitin-Protein Ligases; Formaldehyde; Aldehydes; RNA, Messenger
PubMed: 37951215
DOI: 10.1016/j.molcel.2023.10.011 -
Clinical Epigenetics Oct 2023Multiple mechanisms are involved in kidney damage, among which the role of epigenetic modifications in the occurrence and development of kidney diseases is constantly... (Review)
Review
Multiple mechanisms are involved in kidney damage, among which the role of epigenetic modifications in the occurrence and development of kidney diseases is constantly being revealed. However, N6-methyladenosine (M6A), a well-known post-transcriptional modification, has been regarded as the most prevalent epigenetic modifications in higher eukaryotic, which is involved in various biological processes of cells such as maintaining the stability of mRNA. The role of M6A modification in the mechanism of kidney damage has attracted widespread attention. In this review, we mainly summarize the role of M6A modification in the progression of kidney diseases from the following aspects: the regulatory pattern of N6-methyladenosine, the critical roles of N6-methyladenosine in chronic kidney disease, acute kidney injury and renal cell carcinoma, and then reveal its potential significance in the diagnosis and treatment of various kidney diseases. A better understanding of this field will be helpful for future research and clinical treatment of kidney diseases.
Topics: Humans; DNA Methylation; RNA, Messenger; Kidney; Kidney Diseases
PubMed: 37865763
DOI: 10.1186/s13148-023-01586-7 -
Life Science Alliance Jan 2024Protein-RNA complexes exist in many forms within the cell, from stable machines such as the ribosome to transient assemblies like the spliceosome. All protein-RNA... (Review)
Review
Protein-RNA complexes exist in many forms within the cell, from stable machines such as the ribosome to transient assemblies like the spliceosome. All protein-RNA assemblies rely on spatially and temporally coordinated interactions between specific proteins and RNAs to achieve a functional form. RNA folding and structure are often critical for successful protein binding and protein-RNA complex formation. RNA modifications change the chemical nature of a given RNA and often alter its folding kinetics. Both these alterations can affect how and if proteins or other RNAs can interact with the modified RNA and assemble into complexes. N-methyladenosine (mA) is the most common base modification on mRNAs and regulatory noncoding RNAs and has been shown to impact RNA structure and directly modulate protein-RNA interactions. In this review, focusing on the mechanisms and available quantitative information, we discuss first how the METTL3/14 mA writer complex is specifically targeted to RNA assisted by protein-RNA and other interactions to enable site-specific and co-transcriptional RNA modification and, once introduced, how the mA modification affects RNA folding and protein-RNA interactions.
Topics: RNA; RNA, Messenger; RNA, Untranslated; Protein Binding; Ribosomes
PubMed: 37935465
DOI: 10.26508/lsa.202302240 -
Nature Structural & Molecular Biology Nov 2023In the arms race between bacteria and bacteriophages (phages), some large-genome jumbo phages have evolved a protein shell that encloses their replicating genome to...
In the arms race between bacteria and bacteriophages (phages), some large-genome jumbo phages have evolved a protein shell that encloses their replicating genome to protect it against host immune factors. By segregating the genome from the host cytoplasm, however, the 'phage nucleus' introduces the need to specifically translocate messenger RNA and proteins through the nuclear shell and to dock capsids on the shell for genome packaging. Here, we use proximity labeling and localization mapping to systematically identify proteins associated with the major nuclear shell protein chimallin (ChmA) and other distinctive structures assembled by these phages. We identify six uncharacterized nuclear-shell-associated proteins, one of which directly interacts with self-assembled ChmA. The structure and protein-protein interaction network of this protein, which we term ChmB, suggest that it forms pores in the ChmA lattice that serve as docking sites for capsid genome packaging and may also participate in messenger RNA and/or protein translocation.
Topics: Bacteriophages; Protein Interaction Maps; Capsid; Capsid Proteins; RNA, Messenger
PubMed: 37667030
DOI: 10.1038/s41594-023-01094-5 -
Human Molecular Genetics May 2024Human mitochondrial DNA is one of the most simplified cellular genomes and facilitates compartmentalized gene expression. Within the organelle, there is no physical... (Review)
Review
Human mitochondrial DNA is one of the most simplified cellular genomes and facilitates compartmentalized gene expression. Within the organelle, there is no physical barrier to separate transcription and translation, nor is there evidence that quality control surveillance pathways are active to prevent translation on faulty mRNA transcripts. Mitochondrial ribosomes synthesize 13 hydrophobic proteins that require co-translational insertion into the inner membrane of the organelle. To maintain the integrity of the inner membrane, which is essential for organelle function, requires responsive quality control mechanisms to recognize aberrations in protein synthesis. In this review, we explore how defects in mitochondrial protein synthesis can arise due to the culmination of inherent mistakes that occur throughout the steps of gene expression. In turn, we examine the stepwise series of quality control processes that are needed to eliminate any mistakes that would perturb organelle homeostasis. We aim to provide an integrated view on the quality control mechanisms of mitochondrial protein synthesis and to identify promising avenues for future research.
Topics: Humans; Protein Biosynthesis; Mitochondrial Proteins; Mitochondria; DNA, Mitochondrial; RNA, Messenger; Mitochondrial Ribosomes; Animals
PubMed: 38280230
DOI: 10.1093/hmg/ddae012 -
Journal of Genetics and Genomics = Yi... Apr 2024Messenger RNA (mRNA) translation consists of initiation, elongation, termination, and ribosome recycling, carried out by the translation machinery, primarily including... (Review)
Review
Messenger RNA (mRNA) translation consists of initiation, elongation, termination, and ribosome recycling, carried out by the translation machinery, primarily including tRNAs, ribosomes, and translation factors (TrFs). Translational regulators transduce signals of growth and development, as well as biotic and abiotic stresses, to the translation machinery, where global or selective translational control occurs to modulate mRNA translation efficiency (TrE). As the basis of translational control, the translation machinery directly determines the quality and quantity of newly synthesized peptides and, ultimately, the cellular adaption. Thus, regulating the availability of diverse machinery components is reviewed as the central strategy of translational control. We provide classical signaling pathways (e.g., integrated stress responses) and cellular behaviors (e.g., liquid-liquid phase separation) to exemplify this strategy within different physiological contexts, particularly during host-microbe interactions. With new technologies developed, further understanding this strategy will speed up translational medicine and translational agriculture.
Topics: Ribosomes; Proteins; RNA, Messenger; Peptides; Gene Expression Regulation; Protein Biosynthesis
PubMed: 37536497
DOI: 10.1016/j.jgg.2023.07.009 -
MBio Jan 2024messenger RNA (mRNA) vaccines are a key technology in combating existing and emerging infectious diseases. However, the inherent instability of mRNA and the...
messenger RNA (mRNA) vaccines are a key technology in combating existing and emerging infectious diseases. However, the inherent instability of mRNA and the nonspecificity of lipid nanoparticle-encapsulated (LNP) delivery systems result in the need for cold storage and a relatively short-duration immune response to mRNA vaccines. Herein, we develop a novel vaccine in the form of circRNAs encapsulated in LNPs, and the circular structure of the circRNAs enhances their stability. Lyophilization is considered the most effective method for the long-term preservation of RNA vaccines. However, this process may result in irreversible damage to the nanoparticles, particularly the potential disruption of targeting modifications on LNPs. During the selection of lymph node-targeting ligands, we found that LNPs modified with mannose maintained their physical properties almost unchanged after lyophilization. Additionally, the targeting specificity and immunogenicity remained unaffected. In contrast, even with the addition of cryoprotectants such as sucrose, the physical properties of LNPs were impaired, leading to an obvious decrease in immunogenicity. This may be attributed to the protective role of mannose on the surface of LNPs during lyophilization. Freshly prepared and lyophilized mLNP-circRNA vaccines elicited comparable immune responses in both the rabies virus model and the SARS-CoV-2 model. Our data demonstrated that mLNP-circRNA vaccines elicit robust immune responses while improving stability after lyophilization, with no compromise in tissue targeting specificity. Therefore, mannose-modified LNP-circRNA vaccines represent a promising vaccine design strategy.
Topics: RNA, Circular; Mannose; Vaccines; Immunity; Freeze Drying; RNA, Messenger
PubMed: 38078742
DOI: 10.1128/mbio.01775-23 -
Molecular Cell Aug 2023Cells tightly regulate mRNA processing, localization, and stability to ensure accurate gene expression in diverse cellular states and conditions. Most of these... (Review)
Review
Cells tightly regulate mRNA processing, localization, and stability to ensure accurate gene expression in diverse cellular states and conditions. Most of these regulatory steps have traditionally been thought to occur before translation by the action of RNA-binding proteins. Several recent discoveries highlight multiple co-translational mechanisms that modulate mRNA translation, localization, processing, and stability. These mechanisms operate by recognition of the nascent protein, which is necessarily coupled to its encoding mRNA during translation. Hence, the distinctive sequence or structure of a particular nascent chain can recruit recognition factors with privileged access to the corresponding mRNA in an otherwise crowded cellular environment. Here, we draw on both well-established and recent examples to provide a conceptual framework for how cells exploit nascent protein recognition to direct mRNA fate. These mechanisms allow cells to dynamically and specifically regulate their transcriptomes in response to changes in cellular states to maintain protein homeostasis.
Topics: Peptides; Proteostasis; RNA Processing, Post-Transcriptional; RNA, Messenger; Transcriptome
PubMed: 37595554
DOI: 10.1016/j.molcel.2023.07.014