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Wiley Interdisciplinary Reviews. RNA Nov 2018Eukaryotic RNA can carry more than 100 different types of chemical modifications. Early studies have been focused on modifications of highly abundant RNA, such as... (Review)
Review
Eukaryotic RNA can carry more than 100 different types of chemical modifications. Early studies have been focused on modifications of highly abundant RNA, such as ribosomal RNA and transfer RNA, but recent technical advances have made it possible to also study messenger RNA (mRNA). Subsequently, mRNA modifications, namely methylation, have emerged as key players in eukaryotic gene expression regulation. The most abundant and widely studied internal mRNA modification is N -methyladenosine (m A), but the list of mRNA chemical modifications continues to grow as fast as interest in this field. Over the past decade, transcriptome-wide studies combined with advanced biochemistry and the discovery of methylation writers, readers, and erasers revealed roles for mRNA methylation in the regulation of nearly every aspect of the mRNA life cycle and in diverse cellular, developmental, and disease processes. Although large parts of mRNA function are linked to its cytoplasmic stability and regulation of its translation, a number of studies have begun to provide evidence for methylation-regulated nuclear processes. In this review, we summarize the recent advances in RNA methylation research and highlight how these new findings have contributed to our understanding of methylation-dependent RNA processing in the nucleus. This article is categorized under: RNA Processing > RNA Editing and Modification RNA Processing > Splicing Regulation/Alternative Splicing RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.
Topics: Animals; Cell Nucleus; Epigenesis, Genetic; Humans; Methylation; RNA Precursors; RNA, Messenger; Transcriptome
PubMed: 29921017
DOI: 10.1002/wrna.1489 -
The International Journal of... Sep 2023The faithful splicing of pre-mRNA is critical for accurate gene expression. Dysregulation of pre-mRNA splicing has been associated with several human diseases including... (Review)
Review
The faithful splicing of pre-mRNA is critical for accurate gene expression. Dysregulation of pre-mRNA splicing has been associated with several human diseases including cancer. The ubiquitin-like protein Hub1/UBL5 binds to the substrates non-covalently and promotes pre-mRNA splicing. Additionally, UBL5 promotes the common fragile sites stability and the Fanconi anemia pathway of DNA damage repair. These functions strongly suggests that UBL5 could potentially be implicated in cancer. Therefore, we analyzed the UBL5 expression in TCGA tumor sample datasets and observed the differences between tumor and normal tissues among different tumor subtypes. We have noticed the alteration frequency of UBL5 in TCGA tumor samples. Altogether, this review summarizes the UBL5 functions and discusses its putative role in tumorigenesis.
Topics: Humans; RNA Precursors; RNA Splicing; Ubiquitins
PubMed: 37453225
DOI: 10.1016/j.biocel.2023.106445 -
Methods (San Diego, Calif.) Aug 2017Crystallography is a powerful tool to determine the atomic structures of proteins and RNAs. X-ray crystallography has been used to determine the structure of many... (Review)
Review
Crystallography is a powerful tool to determine the atomic structures of proteins and RNAs. X-ray crystallography has been used to determine the structure of many splicing related proteins and RNAs, making major contributions to our understanding of the molecular mechanism and regulation of pre-mRNA splicing. Compared to other structural methods, crystallography has its own advantage in the high-resolution structural information it can provide and the unique biological questions it can answer. In addition, two new crystallographic methods - the serial femtosecond crystallography and 3D electron crystallography - were developed to overcome some of the limitations of traditional X-ray crystallography and broaden the range of biological problems that crystallography can solve. This review discusses the theoretical basis, instrument requirements, troubleshooting, and exciting potential of these crystallographic methods to further our understanding of pre-mRNA splicing, a critical event in gene expression of all eukaryotes.
Topics: Crystallography, X-Ray; Microscopy, Electron, Transmission; Nanoparticles; Nucleic Acid Conformation; RNA Precursors; RNA Splicing
PubMed: 28506657
DOI: 10.1016/j.ymeth.2017.04.023 -
Current Opinion in Structural Biology Aug 2022In eukaryotes, the expression of genetic information begins in the cell nucleus with precursor messenger RNA (pre-mRNA) transcription and processing into mature mRNA.... (Review)
Review
In eukaryotes, the expression of genetic information begins in the cell nucleus with precursor messenger RNA (pre-mRNA) transcription and processing into mature mRNA. The mRNA is subsequently recognized and packaged by proteins into an mRNA ribonucleoprotein complex (mRNP) and exported to the cytoplasm for translation. Each of the nuclear mRNA maturation steps is carried out by a dedicated molecular machine. Here, we highlight recent structural and mechanistic insights into how these machines function, including the capping enzyme, the spliceosome, the 3'-end processing machinery, and the transcription-export complex. While we increasingly understand individual steps of nuclear gene expression, many questions remain. For example, we are only beginning to reveal how mature mRNAs are recognized and packaged for nuclear export and how mRNA maturation events are coupled to transcription and to each other. Advances in the preparation of recombinant and endogenous protein-nucleic acid complexes, cryo-electron microscopy, and machine learning promise exciting insights into the mechanisms of nuclear gene expression and its spatial organization.
Topics: Active Transport, Cell Nucleus; Cell Nucleus; Cryoelectron Microscopy; RNA Precursors; RNA Transport; RNA, Messenger
PubMed: 35930970
DOI: 10.1016/j.sbi.2022.102431 -
Molecular Cell Apr 2023Removal of the intron from precursor-tRNA (pre-tRNA) is essential in all three kingdoms of life. In humans, this process is mediated by the tRNA splicing endonuclease...
Removal of the intron from precursor-tRNA (pre-tRNA) is essential in all three kingdoms of life. In humans, this process is mediated by the tRNA splicing endonuclease (TSEN) comprising four subunits: TSEN2, TSEN15, TSEN34, and TSEN54. Here, we report the cryo-EM structures of human TSEN bound to full-length pre-tRNA in the pre-catalytic and post-catalytic states at average resolutions of 2.94 and 2.88 Å, respectively. Human TSEN features an extended surface groove that holds the L-shaped pre-tRNA. The mature domain of pre-tRNA is recognized by conserved structural elements of TSEN34, TSEN54, and TSEN2. Such recognition orients the anticodon stem of pre-tRNA and places the 3'-splice site and 5'-splice site into the catalytic centers of TSEN34 and TSEN2, respectively. The bulk of the intron sequences makes no direct interaction with TSEN, explaining why pre-tRNAs of varying introns can be accommodated and cleaved. Our structures reveal the molecular ruler mechanism of pre-tRNA cleavage by TSEN.
Topics: Humans; Introns; RNA Precursors; Endoribonucleases; RNA, Transfer; RNA Splice Sites; RNA Splicing; Nucleic Acid Conformation; Endonucleases
PubMed: 37028420
DOI: 10.1016/j.molcel.2023.03.015 -
Genes Oct 2023Since the discovery of RNA splicing as a fundamental step to remove introns from pre-mRNA to produce mature mRNAs, substantial research in the past decades has...
Since the discovery of RNA splicing as a fundamental step to remove introns from pre-mRNA to produce mature mRNAs, substantial research in the past decades has highlighted RNA splicing as a critical mediator of gene expression and proteome diversity, also being important in many developmental and biological processes [...].
Topics: Humans; RNA Splicing; RNA Precursors; Neoplasms; RNA, Messenger; Introns
PubMed: 38002963
DOI: 10.3390/genes14112020 -
Cellular and Molecular Life Sciences :... Aug 2017Expression of protein-coding genes in eukaryotes relies on the coordinated action of many sophisticated molecular machineries. Transcription produces precursor mRNAs... (Review)
Review
Expression of protein-coding genes in eukaryotes relies on the coordinated action of many sophisticated molecular machineries. Transcription produces precursor mRNAs (pre-mRNAs) and the active gene provides an environment in which the pre-mRNAs are processed, folded, and assembled into RNA-protein (RNP) complexes. The dynamic pre-mRNPs incorporate the growing transcript, proteins, and the processing machineries, as well as the specific protein marks left after processing that are essential for export and the cytoplasmic fate of the mRNPs. After release from the gene, the mRNPs move by diffusion within the interchromatin compartment, making up pools of mRNPs. Here, splicing and polyadenylation can be completed and the mRNPs recruit the major export receptor NXF1. Export competent mRNPs interact with the nuclear pore complex, leading to export, concomitant with compositional and conformational changes of the mRNPs. We summarize the integrated nuclear processes involved in the formation and export of mRNPs.
Topics: Active Transport, Cell Nucleus; Animals; Chromatin; Humans; Nuclear Pore; Polyadenylation; Protein Transport; RNA Precursors; RNA Splicing; RNA, Messenger; Ribonucleoproteins; Transcriptional Activation
PubMed: 28314893
DOI: 10.1007/s00018-017-2503-3 -
RNA Biology Nov 2021U1 snRNP is one of the most abundant ribonucleoprotein (RNP) complexes in eukaryotic cells and is estimated to be approximately 1 million copies per cell. Apart from its... (Review)
Review
U1 snRNP is one of the most abundant ribonucleoprotein (RNP) complexes in eukaryotic cells and is estimated to be approximately 1 million copies per cell. Apart from its canonical role in mRNA splicing, this complex has emerged as a key regulator of eukaryotic mRNA length via inhibition of mRNA 3'-end processing at numerous intronic polyadenylation sites, in a process that is also termed 'U1 snRNP telescripting'. Several reviews have extensively described the concept of U1 telescripting and subsequently highlighted its potential impacts in mRNA metabolism. Here, we review what is currently known regarding the underlying mechanisms of this important phenomenon and discuss open questions and future challenges.
Topics: Animals; Humans; Polyadenylation; RNA Precursors; RNA Splicing; RNA, Messenger; Ribonucleoprotein, U1 Small Nuclear
PubMed: 33416026
DOI: 10.1080/15476286.2021.1872963 -
Cell Reports Dec 2023Argonaute (AGO) proteins execute microRNA (miRNA)-mediated gene silencing. However, it is unclear whether all 4 mammalian AGO proteins (AGO1, AGO2, AGO3, and AGO4) are...
Argonaute (AGO) proteins execute microRNA (miRNA)-mediated gene silencing. However, it is unclear whether all 4 mammalian AGO proteins (AGO1, AGO2, AGO3, and AGO4) are required for miRNA activity. We generate Ago1, Ago3, and Ago4-deficient mice (Ago134) and find AGO1/3/4 to be redundant for miRNA biogenesis, homeostasis, or function, a role that is carried out by AGO2. Instead, AGO1/3/4 regulate the expansion of type 2 immunity via precursor mRNA splicing in CD4 T helper (Th) lymphocytes. Gain- and loss-of-function experiments demonstrate that nuclear AGO3 interacts directly with SF3B3, a component of the U2 spliceosome complex, to aid global mRNA splicing, and in particular the isoforms of the gene Nisch, resulting in a dysregulated Nisch isoform ratio. This work uncouples AGO1, AGO3, and AGO4 from miRNA-mediated RNA interference, identifies an AGO3:SF3B3 complex in the nucleus, and reveals a mechanism by which AGO proteins regulate inflammatory diseases.
Topics: Animals; Mice; Argonaute Proteins; Imidazoline Receptors; Mammals; MicroRNAs; RNA Interference; RNA Precursors; RNA Splicing; RNA, Messenger
PubMed: 38096048
DOI: 10.1016/j.celrep.2023.113515 -
The FEBS Journal Nov 2021Cancer is a leading cause of death and a major health problem worldwide, particularly in more developed countries. There is, therefore, an urgent clinical need to...
Cancer is a leading cause of death and a major health problem worldwide, particularly in more developed countries. There is, therefore, an urgent clinical need to develop more effective therapies to treat cancer and metastatic disease. In this Editorial, the content of The FEBS Journal's Special Issue on Cancer Therapeutics is outlined. The interesting collection of recent articles in this issue covers a wide repertoire of cancer therapeutic approaches. While some of the articles discuss broad-spectrum applications such as immunotherapy and oncolytic virus therapy, others focus on a particular type of cancer or a signalling pathway that has gone awry such as aberrant Ca signalling, glycosylation or pre-mRNA processing. Finally, an article featured in this issue reviews our current understanding of how cancer cells can become dormant, often for decades, and which pathways reactivate these cells to cause relapse. I am sure there is something for everyone in this issue.
Topics: Calcium; Glycosylation; Humans; RNA Precursors
PubMed: 34719877
DOI: 10.1111/febs.16228