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Advanced Drug Delivery Reviews Jun 2015The discovery of the first microRNA (miRNA) over 20 years ago has ushered in a new era in molecular biology. There are now over 2000 miRNAs that have been discovered in... (Review)
Review
The discovery of the first microRNA (miRNA) over 20 years ago has ushered in a new era in molecular biology. There are now over 2000 miRNAs that have been discovered in humans and it is believed that they collectively regulate one third of the genes in the genome. miRNAs have been linked to many human diseases and are being pursued as clinical diagnostics and as therapeutic targets. This review presents an overview of the miRNA pathway, including biogenesis routes, biological roles, and clinical approaches.
Topics: Animals; Drug Discovery; Humans; Metabolic Diseases; MicroRNAs; Molecular Targeted Therapy; Neoplasms; Oligonucleotides, Antisense; RNA Interference; Ribonuclease III
PubMed: 25979468
DOI: 10.1016/j.addr.2015.05.001 -
DICER1 tumor predisposition syndrome: an evolving story initiated with the pleuropulmonary blastoma.Modern Pathology : An Official Journal... Jan 2022DICER1 syndrome (OMIM 606241, 601200) is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous DICER1 germline mutation. The most common... (Review)
Review
DICER1 syndrome (OMIM 606241, 601200) is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous DICER1 germline mutation. The most common tumor seen clinically is the pleuropulmonary blastoma (PPB), a lung neoplasm of early childhood which is classified on its morphologic features into four types (IR, I, II and III) with tumor progression over time within the first 4-5 years of life from the prognostically favorable cystic type I to the unfavorable solid type III. Following the initial report of PPB, its association with other cystic neoplasms was demonstrated in family studies. The detection of the germline mutation in DICER1 provided the opportunity to identify and continue to recognize a number seemingly unrelated extrapulmonary neoplasms: Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcomas of the cervix and other sites, multinodular goiter, differentiated and poorly differentiated thyroid carcinoma, cervical-thyroid teratoma, cystic nephroma-anaplastic sarcoma of kidney, nasal chondromesenchymal hamartoma, intestinal juvenile-like hamartomatous polyp, ciliary body medulloepithelioma, pituitary blastoma, pineoblastoma, primary central nervous system sarcoma, embryonal tumor with multilayered rosettes-like cerebellar tumor, PPB-like peritoneal sarcoma, DICER1-associated presacral malignant teratoid neoplasm and other non-neoplastic associations. Each of these neoplasms is characterized by a second somatic mutation in DICER1. In this review, we have summarized the salient clinicopathologic aspects of these tumors whose histopathologic features have several overlapping morphologic attributes particularly the primitive mesenchyme often with rhabdomyoblastic and chondroid differentiation and an uncommitted spindle cell pattern. Several of these tumors have an initial cystic stage from which there is progression to a high grade, complex patterned neoplasm. These pathologic findings in the appropriate clinical setting should serve to alert the pathologist to the possibility of a DICER1-associated neoplasm and initiate appropriate testing on the neoplasm and to alert the clinician about the concern for a DICER1 mutation.
Topics: Causality; Germ-Line Mutation; Humans; Lung Neoplasms; Pleural Neoplasms; Pulmonary Blastoma; Ribonuclease III; Syndrome
PubMed: 34599283
DOI: 10.1038/s41379-021-00905-8 -
Nature Reviews. Molecular Cell Biology Feb 2016Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. This A-to-I editing occurs not only in protein-coding regions of mRNAs,... (Review)
Review
Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. This A-to-I editing occurs not only in protein-coding regions of mRNAs, but also frequently in non-coding regions that contain inverted Alu repeats. Editing of coding sequences can result in the expression of functionally altered proteins that are not encoded in the genome, whereas the significance of Alu editing remains largely unknown. Certain microRNA (miRNA) precursors are also edited, leading to reduced expression or altered function of mature miRNAs. Conversely, recent studies indicate that ADAR1 forms a complex with Dicer to promote miRNA processing, revealing a new function of ADAR1 in the regulation of RNA interference.
Topics: Adenosine; Adenosine Deaminase; Alu Elements; Animals; Caenorhabditis elegans; Drosophila melanogaster; Genome; Humans; Inosine; Isoenzymes; MicroRNAs; RNA Editing; RNA, Messenger; Ribonuclease III; Signal Transduction
PubMed: 26648264
DOI: 10.1038/nrm.2015.4 -
Nucleic Acids Research Sep 2023MicroRNAs are sequentially processed by RNase III enzymes Drosha and Dicer. miR-451 is a highly conserved miRNA in vertebrates which bypasses Dicer processing and...
MicroRNAs are sequentially processed by RNase III enzymes Drosha and Dicer. miR-451 is a highly conserved miRNA in vertebrates which bypasses Dicer processing and instead relies on AGO2 for its maturation. miR-451 is highly expressed in erythrocytes and regulates the differentiation of erythroblasts into mature red blood cells. However, the mechanistic details underlying miR-451 biogenesis in erythrocytes remains obscure. Here, we report that the RNA binding protein CSDE1 which is required for the development of erythroblasts into erythrocytes, controls the expression of miR-451 in erythroleukemia cells. CSDE1 binds miR-451 and regulates AGO2 processing of pre-miR-451 through its N-terminal domains. CSDE1 further interacts with PARN and promotes the trimming of intermediate miR-451 to the mature length. Together, our results demonstrate that CSDE1 promotes biogenesis of miR-451 in erythroid progenitors.
Topics: Animals; MicroRNAs; Ribonuclease III; RNA-Binding Proteins; Humans
PubMed: 37493604
DOI: 10.1093/nar/gkad619 -
Nature Reviews. Genetics May 2020RNA interference (RNAi), a cellular process through which small RNAs target and regulate complementary RNA transcripts, has well-characterized roles in... (Review)
Review
RNA interference (RNAi), a cellular process through which small RNAs target and regulate complementary RNA transcripts, has well-characterized roles in post-transcriptional gene regulation and transposon repression. Recent studies have revealed additional conserved roles for RNAi proteins, such as Argonaute and Dicer, in chromosome function. By guiding chromatin modification, RNAi components promote chromosome segregation during both mitosis and meiosis and regulate chromosomal and genomic dosage response. Small RNAs and the RNAi machinery also participate in the resolution of DNA damage. Interestingly, many of these lesser-studied functions seem to be more strongly conserved across eukaryotes than are well-characterized functions such as the processing of microRNAs. These findings have implications for the evolution of RNAi since the last eukaryotic common ancestor, and they provide a more complete view of the functions of RNAi.
Topics: Animals; Argonaute Proteins; Centromere; Chromosomes; DEAD-box RNA Helicases; Evolution, Molecular; Humans; RNA Interference; Ribonuclease III
PubMed: 32051563
DOI: 10.1038/s41576-019-0203-6 -
FEBS Letters Jun 2018MicroRNAs (miRNAs) are evolutionarily conserved small regulatory RNAs that participate in the adjustment of many, if not all, fundamental biological processes. Molecular... (Review)
Review
MicroRNAs (miRNAs) are evolutionarily conserved small regulatory RNAs that participate in the adjustment of many, if not all, fundamental biological processes. Molecular mechanisms involved in miRNA biogenesis and mode of action have been elucidated in the past two decades. Similar to many cellular pathways, miRNA processing and function can be globally or specifically regulated at several levels and by numerous proteins and RNAs. Given their role as fine-tuning molecules, it is essential for miRNA expression to be tightly regulated in order to maintain cellular homeostasis. Here, we review our current knowledge of the first step of their maturation occurring in the nucleus and how it can be specifically and dynamically modulated.
Topics: Animals; Cell Nucleus; Gene Expression Regulation; Homeostasis; Humans; MicroRNAs; Models, Molecular; RNA Polymerase II; Ribonuclease III
PubMed: 29683487
DOI: 10.1002/1873-3468.13067 -
Cancer Cytopathology Oct 2020
Topics: DEAD-box RNA Helicases; Humans; Mutation; Ribonuclease III; Thyroid Diseases
PubMed: 32897630
DOI: 10.1002/cncy.22327 -
International Journal of Molecular... Jan 2021Ribonuclease Dicer belongs to the family of RNase III endoribonucleases, the enzymes that specifically hydrolyze phosphodiester bonds found in double-stranded regions of... (Review)
Review
Ribonuclease Dicer belongs to the family of RNase III endoribonucleases, the enzymes that specifically hydrolyze phosphodiester bonds found in double-stranded regions of RNAs. Dicer enzymes are mostly known for their essential role in the biogenesis of small regulatory RNAs. A typical Dicer-type RNase consists of a helicase domain, a domain of unknown function (DUF283), a PAZ (Piwi-Argonaute-Zwille) domain, two RNase III domains, and a double-stranded RNA binding domain; however, the domain composition of Dicers varies among species. Dicer and its homologues developed only in eukaryotes; nevertheless, the two enzymatic domains of Dicer, helicase and RNase III, display high sequence similarity to their prokaryotic orthologs. Evolutionary studies indicate that a combination of the helicase and RNase III domains in a single protein is a eukaryotic signature and is supposed to be one of the critical events that triggered the consolidation of the eukaryotic RNA interference. In this review, we provide the genetic insight into the domain organization and structure of Dicer proteins found in vertebrate and invertebrate animals, plants and fungi. We also discuss, in the context of the individual domains, domain deletion variants and partner proteins, a variety of Dicers' functions not only related to small RNA biogenesis pathways.
Topics: Animals; Evolution, Molecular; Fungi; Gene Deletion; Humans; Models, Molecular; Plants; Protein Conformation; Protein Domains; Ribonuclease III
PubMed: 33435485
DOI: 10.3390/ijms22020616 -
Genomics Sep 2020MicroRNAs (miRNAs) are small endogenous non-coding RNAs in eukaryotes which regulate the expression of numerous genes post-transcriptionally, thereby playing critical... (Review)
Review
MicroRNAs (miRNAs) are small endogenous non-coding RNAs in eukaryotes which regulate the expression of numerous genes post-transcriptionally, thereby playing critical roles in cells and organismal development. The high-throughput sequencing technologies enable the effective detection and annotation of miRNAs. Several miRNA variants with heterogeneous ends, lengths, and sequences can be generated from a single miRNA locus. Discovery of these miRNA variants, also known as miRNA isoforms or isomiRs, has made our understanding of the cells' miRNome deeper than previously pictured. Despite their wide presence in multiple datasets, the different possible origins and true biological significance of isomiRs are yet to be uncovered. Several recent emerging studies suggest that isomiRs are biologically active and non-randomly formed. This review aims to provide a comprehensive insight into the origins and biological importance of isomiRs, highlighting the enormous complexity of miRNA regulatory networks which broadens our knowledge about the post-transcriptional gene regulation in plants.
Topics: MicroRNAs; Plant Proteins; RNA Editing; RNA Precursors; RNA, Plant; Ribonuclease III
PubMed: 32561347
DOI: 10.1016/j.ygeno.2020.06.019 -
EMBO Reports Jul 2023RNase III Dicer produces small RNAs guiding sequence-specific regulations, with important biological roles in eukaryotes. Major Dicer-dependent mechanisms are RNA... (Review)
Review
RNase III Dicer produces small RNAs guiding sequence-specific regulations, with important biological roles in eukaryotes. Major Dicer-dependent mechanisms are RNA interference (RNAi) and microRNA (miRNA) pathways, which employ distinct types of small RNAs. Small interfering RNAs (siRNAs) for RNAi are produced by Dicer from long double-stranded RNA (dsRNA) as a pool of different small RNAs. In contrast, miRNAs have specific sequences because they are precisely cleaved out from small hairpin precursors. Some Dicer homologs efficiently generate both, siRNAs and miRNAs, while others are adapted for biogenesis of one small RNA type. Here, we review the wealth of recent structural analyses of animal and plant Dicers, which have revealed how different domains and their adaptations contribute to substrate recognition and cleavage in different organisms and pathways. These data imply that siRNA generation was Dicer's ancestral role and that miRNA biogenesis relies on derived features. While the key element of functional divergence is a RIG-I-like helicase domain, Dicer-mediated small RNA biogenesis also documents the impressive functional versatility of the dsRNA-binding domain.
Topics: Animals; Ribonuclease III; RNA, Small Interfering; MicroRNAs; RNA, Double-Stranded; RNA Interference
PubMed: 37310138
DOI: 10.15252/embr.202357215