-
Wiley Interdisciplinary Reviews. RNA Sep 2016The process of removing intronic sequences from a precursor to messenger RNA (pre-mRNA) to yield a mature mRNA transcript via splicing is an integral step in eukaryotic... (Review)
Review
The process of removing intronic sequences from a precursor to messenger RNA (pre-mRNA) to yield a mature mRNA transcript via splicing is an integral step in eukaryotic gene expression. Splicing is carried out by a cellular nanomachine called the spliceosome that is composed of RNA components and dozens of proteins. Despite decades of study, many fundamentals of spliceosome function have remained elusive. Recent developments in single-molecule fluorescence microscopy have afforded new tools to better probe the spliceosome and the complex, dynamic process of splicing by direct observation of single molecules. These cutting-edge technologies enable investigators to monitor the dynamics of specific splicing components, whole spliceosomes, and even cotranscriptional splicing within living cells. WIREs RNA 2016, 7:683-701. doi: 10.1002/wrna.1358 For further resources related to this article, please visit the WIREs website.
Topics: Eukaryota; Microscopy, Fluorescence; RNA Precursors; Single Molecule Imaging; Spliceosomes; Staining and Labeling
PubMed: 27198613
DOI: 10.1002/wrna.1358 -
A matter of maturity: The impact of pre-mRNA processing in gene expression and antigen presentation.The International Journal of... Oct 2017RNA processing plays a pivotal role in the diversification of high eukaryotes transcriptome and proteome. The expression of gene products controlling a variety of... (Review)
Review
RNA processing plays a pivotal role in the diversification of high eukaryotes transcriptome and proteome. The expression of gene products controlling a variety of cellular and physiological processes depends largely on a complex maturation process undergone by pre-mRNAs to become translation-competent mRNAs. Here we review the different mechanisms involved in the pre-mRNA processing and disclose their impact in the gene regulation process in eukaryotic cells. We describe some viral strategies targeting pre-mRNA processing to control gene expression and host immune response and discuss their relevance as tools for a better understanding of cell biology. Finally, we highlight accumulating evidences toward the occurrence of a translation event coupled to mRNA biogenesis in the nuclear compartment and argue how this is relevant for the production of antigenic peptide substrates for the major histocompatibility complex class I pathway.
Topics: Animals; Antigen Presentation; Cell Nucleus; Gene Expression Regulation; Humans; RNA Precursors; RNA Processing, Post-Transcriptional; Virus Diseases
PubMed: 28549625
DOI: 10.1016/j.biocel.2017.05.023 -
Nature Structural & Molecular Biology Dec 2023JTE-607 is an anticancer and anti-inflammatory compound and its active form, compound 2, directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in...
JTE-607 is an anticancer and anti-inflammatory compound and its active form, compound 2, directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-messenger RNA (pre-mRNA) 3' processing. Surprisingly, compound 2-mediated inhibition of pre-mRNA cleavage is sequence specific and the drug sensitivity is predominantly determined by sequences flanking the cleavage site (CS). Using massively parallel in vitro assays, we identified key sequence features that determine drug sensitivity. We trained a machine learning model that can predict poly(A) site (PAS) relative sensitivity to compound 2 and provide the molecular basis for understanding the impact of JTE-607 on PAS selection and transcription termination genome wide. We propose that CPSF73 and associated factors bind to the CS region in a sequence-dependent manner and the interaction affinity determines compound 2 sensitivity. These results have not only elucidated the mechanism of action of JTE-607, but also unveiled an evolutionarily conserved sequence specificity of the mRNA 3' processing machinery.
Topics: Cell Line; RNA Precursors; RNA Processing, Post-Transcriptional; RNA, Messenger
PubMed: 38087090
DOI: 10.1038/s41594-023-01161-x -
Drug Discovery Today Jan 2023The concept of using small molecules to therapeutically modulate pre-mRNA splicing was validated with the US Food and Drug Administration (FDA) approval of Evrysdi®... (Review)
Review
The concept of using small molecules to therapeutically modulate pre-mRNA splicing was validated with the US Food and Drug Administration (FDA) approval of Evrysdi® (risdiplam) in 2020. Since then, efforts have continued unabated toward the discovery of new splicing-modulating drugs. However, the drug development world has evolved in the 10 years since risdiplam precursors were first identified in high-throughput screening (HTS). Now, new mechanistic insights into RNA-processing pathways and regulatory networks afford increasingly feasible targeted approaches. In this review, organized into classes of biological target, we compile and summarize small molecules discovered, devised, and developed since 2020 to alter pre-mRNA splicing.
Topics: RNA Precursors; RNA Splicing; Azo Compounds; Pyrimidines; Alternative Splicing
PubMed: 36356786
DOI: 10.1016/j.drudis.2022.103431 -
Journal of Biomedicine & Biotechnology 2009MicroRNAs (miRNAs) are often hosted in introns of protein-coding genes. Given that the same transcriptional unit can potentially give rise to both miRNA and mRNA... (Review)
Review
MicroRNAs (miRNAs) are often hosted in introns of protein-coding genes. Given that the same transcriptional unit can potentially give rise to both miRNA and mRNA transcripts raises the intriguing question of the level of interaction between these processes. Recent studies from transcription, pre-mRNA splicing, and miRNA-processing perspectives have investigated these relationships and yielded interesting, yet somewhat controversial findings. Here we discuss major studies in the field.
Topics: Humans; MicroRNAs; Models, Molecular; RNA Precursors; RNA Splicing; Signal Transduction
PubMed: 19606257
DOI: 10.1155/2009/594678 -
Trends in Pharmacological Sciences Dec 2021RNA splicing, the process by which precursor mRNA (pre-mRNA) is processed to mature mRNA, is catalyzed by the spliceosome. Recently, Chatrikhi et al. identified...
RNA splicing, the process by which precursor mRNA (pre-mRNA) is processed to mature mRNA, is catalyzed by the spliceosome. Recently, Chatrikhi et al. identified pharmacologic means to perturb splicing by enhancing the spliceosome's binding to pre-mRNA. This represents a novel chemical target and mechanism for therapeutic modulation of splicing.
Topics: Humans; Mutation; RNA Precursors; RNA Splicing Factors; RNA, Messenger; Spliceosomes
PubMed: 34602305
DOI: 10.1016/j.tips.2021.09.006 -
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 -
Cellular and Molecular Life Sciences :... Sep 2011The human genome contains more than 1,000 microRNA (miRNA) genes, which are transcribed mainly by RNA polymerase II. The canonical pathway of miRNA biogenesis includes... (Review)
Review
The human genome contains more than 1,000 microRNA (miRNA) genes, which are transcribed mainly by RNA polymerase II. The canonical pathway of miRNA biogenesis includes the nuclear processing of primary transcripts (pri-miRNAs) by the ribonuclease Drosha and further cytoplasmic processing of pre-miRNAs by the ribonuclease Dicer. This review discusses the issue of miRNA end heterogeneity generated primarily by Drosha and Dicer cleavage and focuses on the structural aspects of the Dicer step of miRNA biogenesis. We examine the structures of miRNA precursors, both predicted and experimentally determined, as well as the influence of various motifs that disturb the regularity of pre-miRNA structure on Dicer cleavage specificity. We evaluate the structural determinants of the length diversity of miRNA generated by Dicer from different precursors and highlight the importance of asymmetrical motifs. Finally, we discuss the impact of Dicer protein partners on cleavage efficiency and specificity and propose the contribution of pre-miRNA structural plasticity to the dynamics of the dicing complex.
Topics: Humans; MicroRNAs; RNA Precursors; RNA Processing, Post-Transcriptional; Ribonuclease III
PubMed: 21607569
DOI: 10.1007/s00018-011-0726-2 -
Molecular Cell Jul 2005Apoptosis, a phenomenon that allows the regulated destruction and disposal of damaged or unwanted cells, is common to many cellular processes in multicellular organisms.... (Review)
Review
Apoptosis, a phenomenon that allows the regulated destruction and disposal of damaged or unwanted cells, is common to many cellular processes in multicellular organisms. In humans more than 200 proteins are involved in apoptosis, many of which are dysregulated or defective in human diseases including cancer. A large number of apoptotic factors are regulated via alternative splicing, a process that allows for the production of discrete protein isoforms with often distinct functions from a common mRNA precursor. The abundance of apoptosis genes that are alternatively spliced and the often antagonistic roles of the generated protein isoforms strongly imply that alternative splicing is a crucial mechanism for regulating life and death decisions. Importantly, modulation of isoform production of cell death proteins via pharmaceutical manipulation of alternative splicing may open up new therapeutic avenues for the treatment of disease.
Topics: Alternative Splicing; Animals; Apoptosis; Caspases; Gene Expression Regulation; Humans; Models, Biological; Protein Isoforms; RNA Precursors
PubMed: 15989960
DOI: 10.1016/j.molcel.2005.05.026 -
Planta May 2023Serine/arginine-rich (SR) proteins participate in RNA processing by interacting with precursor mRNAs or other splicing factors to maintain plant growth and stress... (Review)
Review
Serine/arginine-rich (SR) proteins participate in RNA processing by interacting with precursor mRNAs or other splicing factors to maintain plant growth and stress responses. Alternative splicing is an important mechanism involved in mRNA processing and regulation of gene expression at the posttranscriptional level, which is the main reason for the diversity of genes and proteins. The process of alternative splicing requires the participation of many specific splicing factors. The SR protein family is a splicing factor in eukaryotes. The vast majority of SR proteins' existence is an essential survival factor. Through its RS domain and other unique domains, SR proteins can interact with specific sequences of precursor mRNA or other splicing factors and cooperate to complete the correct selection of splicing sites or promote the formation of spliceosomes. They play essential roles in the composition and alternative splicing of precursor mRNAs, providing pivotal functions to maintain growth and stress responses in animals and plants. Although SR proteins have been identified in plants for three decades, their evolutionary trajectory, molecular function, and regulatory network remain largely unknown compared to their animal counterparts. This article reviews the current understanding of this gene family in eukaryotes and proposes potential key research priorities for future functional studies.
Topics: Animals; RNA-Binding Proteins; Serine; Nuclear Proteins; RNA Splicing; Alternative Splicing; RNA Precursors; Plant Proteins; RNA, Messenger; RNA Splicing Factors; Arginine
PubMed: 37145304
DOI: 10.1007/s00425-023-04132-0