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The enzyme Dicer is best known for its role as a riboendonuclease in the small RNA pathway. In this canonical role, Dicer is a critical regulator of the biogenesis of microRNA and small interfering RNA, as well as a growing number of additional small RNAs derived from various sources. Emerging evidence demonstrates that Dicer's endonuclease role ex...
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MicroRNAs (miRNAs), a class of 18–25 nucleotide (nt) non-coding RNAs, usually inhibit the expression of their target genes. They are transcribed from endogenous genes and are processed for maturation by multiple pathways. miR-144/451, a bicistronic gene locus, encodes miR-144 and miR-451, both of which are highly conserved in evolution. These two m...
MicroRNAs (miRNAs) are short, non-coding post-transcriptional gene regulators. In mammalian cells, mature miRNAs are produced from primary precursors (pri-miRNAs) using canonical protein machinery, which includes Drosha/DGCR8 and Dicer, or the non-canonical mirtron pathway. In plant cells, mature miRNAs are excised from pri-miRNAs by the DICER-LIKE...
MicroRNAs (miRNAs) are a major class of conserved non-coding RNAs that have a wide range of functions during development and disease. Biogenesis of canonical miRNAs depend on the cytoplasmic processing of pre-miRNAs to mature miRNAs by the Dicer endoribonuclease. Once mature miRNAs are generated, the miRNA-induced silencing complex (miRISC), or miR...
MicroRNAs are evolutionarily conserved small, noncoding RNAs that regulate diverse biological processes. Due to their essential regulatory roles, microRNA biogenesis is tightly regulated, where protein factors are often found to interact with specific primary and precursor microRNAs for regulation. Here, using NMR relaxation dispersion spectroscopy...
MicroRNAs (miRNAs) are a class of short non-coding RNAs (~22 nt) that play important gene-regulatory functions in nearly all biological processes in eukaryotic organisms. Mature miRNAs are loaded into an Argonaute (Ago) protein effector and guide the nucleoprotein complex to recognize and silence target RNAs post-transcriptionally. This chapter out...
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... In the cytoplasm, a helicase enzyme breaks down these exported pre-miRNAs with RNase motif encoded by the DICER1 gene and known as endoribonuclease Dicer to produce double-stranded matured miRNAs in the cytosol [19]. The 5′-end of the 20-22 nucleotides long mature miRNA acts as a guide strand for Argonaute protein which is the central active component of the RISC complex (RNA-induced silencing complex) and targets mRNAs by attaching itself to the 3′-untranslated region (3′-UTR) of mRNA, which has complementary sequences and acts as a potent modulator of gene expression. ...
MicroRNA (miRNA) are usually 18–25 nucleotides long non-coding RNA targeting post-transcriptional regulation of genes involved in various biological processes. The function of miRNA is essential for maintaining a homeostatic cellular condition, regulating autophagy, cellular motility, and inflammation. Dysregulation of miRNA is responsible for multiple disorders, including neurodegeneration, which has emerged as a severe problem in recent times and has verified itself as a life-threatening condition that can be understood by the continuous destruction of neurons affecting various cognitive and motor functions. Parkinson’s disease (PD) is the second most common, permanently debilitating neurodegenerative disorder after Alzheimer’s, mainly characterized by uncontrolled tremor, stiffness, bradykinesia or akinesia (slowness in movement), and post-traumatic stress disorder. PD is mainly caused by the demolition of the primary dopamine neurotransmitter secretory cells and dopaminergic or dopamine secretory neurons in the substantia nigra pars compacta of the midbrain, which are majorly responsible for motor functions. In this study, a systematic evaluation of research articles from year 2017 to 2022 was performed on multiple search engines, and lists of miRNA being dysregulated in PD in different body components were generated. This study highlighted miR-7, miR-124, miR-29 family, and miR-425, showing altered expression levels during PD’s progression, further regulating the expression of multiple genes responsible for PD.
... In neurodegenerative disease, miRNAs play a significant role in neuronal malfunction through an increased buildup of protein and peptides in the pathogenic form [35]. The dicer enzyme in the nucleus is essential in miRNA synthesis [36]. When knocked out of specific areas in the brain, this leads to removing the dicer enzyme, and specific miRNA will affect and not be made, thus leading to the manifestation of neurodegenerative disorders [37]. ...
Neurodegenerative diseases that include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS), arise due to numerous causes like protein accumulation and autoimmunity, characterized by neurologic depletion which lead to incapacity in normal physiological function such as thinking and movement in these patients. Glial cells perform a critical role in protective neuronal function; in the case of neuroinflammation, glial cell dysfunction can promote the development of neurodegenerative diseases. MiRNA participates in gene regulation and plays a vital role in many biological processes in the body; in the central nervous system (CNS), it can play an essential part in neural maturation and differentiation. In neurodegenerative diseases, miRNA dysregulation occurs, enhancing the development of these diseases. In this review, we discuss neurodegenerative diseases (Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)) and how miRNA is preserved as a diagnostic biomarker or therapeutic agent in these disorders. Finally, we highlighted miRNA as therapy.
... In the siRNA and miRNA pathway, long dsRNA and miRNA precursors are processed into 19-25 nucleotide siRNAs or miRNA duplexes by the RNase-III-like enzyme Dicer. 7 Afterward, the siRNA/miRNA binds to the RNAinduced silencing complex (RISC) to degrade homologous mRNAs or affect protein biosynthesis 8 (Fig. 1(A), (B)). In the piRNA pathway, de novo piRNA production begins with the transcription of long single-stranded antisense RNA called the piRNA precursor by RNA polymerase II from particular genomic sites. ...
While the overuse of classical chemical pesticides has had a detrimental impact on the environment and human health, the discovery of RNA interference (RNAi) offered the opportunity to develop new and sustainable approaches for pest management. RNAi is a naturally occurring regulation and defense mechanism that can be exploited to effectively protect crops by silencing key genes affecting the growth, development, behavior or fecundity of pests. However, as with all technologies, there is a range of potential risks and challenges associated with the application of RNAi, such as dsRNA stability, the potential for off‐target effects, the safety of non‐target organisms, and other application challenges. A better understanding of the molecular mechanisms involved in RNAi and in‐depth discussion and analysis of these associated safety risks, is required to limit or mitigate potential adverse effects.
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... Dicer is responsible for the second cleavage step of the canonical miRNA maturation pathway. It is a large multidomain protein that adopts an L-shape structure where the Platform-PAZ-Connector (PPC) cassette is positioned at the top of the "L," the helicase domain forms the base and the two RNase III domains (RIIIDa and RIIIDb) fall in between [16][17][18][19][20][21][22]. This architecture allows Dicer to interact with the extremities of the pre-miRNA hairpins. ...
... These in vitro investigations of Dicer binding and cleavage of let-7 precursors allow us to update current concepts related to Dicer activity toward different substrates, accentuating the broad specificity of this key enzyme in RNA silencing. This broad specificity is likely important for cleavage of a wide variety of other known substrates, such as dsRNAs, Line1 retrotransposons, mRNAs, snoRNAs, tRNAs, and harmful R-loops [16,31,71,72]. ...
The human let-7 miRNA family consists of thirteen members that play critical roles in many biological processes, including development timing and tumor suppression, and their levels are disrupted in several diseases. Dicer is the endoribonuclease responsible for processing the precursor miRNA (pre-miRNA) to yield the mature miRNA, and thereby plays a crucial role in controlling the cellular levels of let-7 miRNAs. It is well established that the sequence and structural features of pre-miRNA hairpins such as the 5′-phosphate, the apical loop, and the 2-nt 3′-overhang are important for the processing activity of Dicer. Exceptionally, nine precursors of the let-7 family (pre-let-7) contain a 1-nt 3′-overhang and get mono-uridylated in vivo, presumably to allow efficient processing by Dicer. Pre-let-7 are also oligo-uridylated in vivo to promote their degradation and likely prevent their efficient processing by Dicer. In this study, we systematically investigated the impact of sequence and structural features of all human let-7 pre-miRNAs, including their 3′-end modifications, on Dicer binding and processing. Through the combination of SHAPE structural probing, in vitro binding and kinetic studies using purified human Dicer, we show that despite structural discrepancies among pre-let-7 RNAs, Dicer exhibits remarkable promiscuity in binding and cleaving these substrates. Moreover, the 1- or 2-nt 3′-overhang, 3′-mono-uridylation, and 3′-oligo-uridylation of pre-let-7 substrates appear to have little effect on Dicer binding and cleavage rates. Thus, this study extends current knowledge regarding the broad substrate specificity of Dicer and provides novel insight regarding the effect of 3′-modifications on binding and cleavage by Dicer.
... Central to RNAi are key components, namely Dicer-like proteins (DCLs), Argonaute proteins (AGOs), and RNA-dependent RNA polymerase, which are exclusively implicated in mediating miRNA-guided gene silencing. DCLs, a class of endonucleases belonging to the RNaseIII family, are primarily localized in the nucleus and initiate the processing of miRNAs [17]. DCLs play a pivotal role in generating 21-24 nt dsRNA fragments that give rise to siRNAs and miRNAs. ...
RNA interference (RNAi) is a conserved molecular mechanism that plays a critical role in post-transcriptional gene silencing across diverse organisms. This review delves into the role of RNAi in plant functional genomics and its applications in crop improvement, highlighting its mechanistic insights and practical implications. The review begins with the foundational discovery of RNAi’s mechanism, tracing its origins from petunias to its widespread presence in various organisms. Various classes of regulatory non-coding small RNAs, including siRNAs, miRNAs, and phasiRNAs, have been uncovered, expanding the scope of RNAi-mediated gene regulation beyond conventional understanding. These RNA classes participate in intricate post-transcriptional and epigenetic processes that influence gene expression. In the context of crop enhancement, RNAi has emerged as a powerful tool for understanding gene functions. It has proven effective in deciphering gene roles related to stress resistance, metabolic pathways, and more. Additionally, RNAi-based approaches hold promise for integrated pest management and sustainable agriculture, contributing to global efforts in food security. This review discusses RNAi’s diverse applications, such as modifying plant architecture, extending shelf life, and enhancing nutritional content in crops. The challenges and future prospects of RNAi technology, including delivery methods and biosafety concerns, are also explored. The global landscape of RNAi research is highlighted, with significant contributions from regions such as China, Europe, and North America. In conclusion, RNAi remains a versatile and pivotal tool in modern plant research, offering novel avenues for understanding gene functions and improving crop traits. Its integration with other biotechnological approaches such as gene editing holds the potential to shape the future of agriculture and sustainable food production.
... MiRNAs are short, non-coding RNAs that are epigenetic regulators of transcription and by extension, translation. MiRNAs are thought to regulate up to 90% of all genes by mainly targeting the 3′ untranslated region of target mRNAs, leading to degradation or inhibition of translation (19,20). Modulation of miRNA expression may be a mecha nism underlying host response to metabolic signals, including those generated from microbial metabolites. ...
The gut microbial ecosystem underlies physiological relationships between the gut and distal organs. Mechanisms remain elusive but rely at least partially on the production of a diverse set of absorbable metabolites and host gene expression regulation. Here we show that in female mice, gut cecal microbiota profiles are related to microRNAs (miRNAs) expressed in the mammary gland. A subset of these miRNAs were found to regulate genes involved in breast cancer-related processes, such as cell proliferation and migration. To determine if these relationships could be exploited toward the reduction of breast cancer risk, we studied if they are modifiable by dietary flaxseed (FS), a source of lignan secoisolariciresinol diglucoside (SDG) and alpha-linolenic acid (ALA)-rich oil (FSO), both with antitumor effects. Importantly, SDG, but not ALA, needs microbial processing to release bioactive metabolites. We found that the microbiota and mammary gland miRNA are related, and FS modifies these relationships toward an antioncogenic phenotype. FSO- and SDG-related miRNAs were found to be involved in different pathways and neither FSO nor SDG alone could recapitulate the effects of whole FS, affecting unique pathways related to extracellular matrix processing. These findings highlight the existence of inter-organ microbiota-miRNA relationships, show that dietary interventions interact to affect them, and suggest a novel route for breast cancer prevention.
IMPORTANCE
Breast cancer is a leading cause of cancer mortality worldwide. There is a growing interest in using dietary approaches, including flaxseed (FS) and its oil and lignan components, to mitigate breast cancer risk. Importantly, there is recognition that pubertal processes and lifestyle, including diet, are important for breast health throughout life. Mechanisms remain incompletely understood. Our research uncovers a link between mammary gland miRNA expression and the gut microbiota in young female mice. We found that this relationship is modifiable via a dietary intervention. Using data from The Cancer Genome Atlas, we also show that the expression of miRNAs involved in these relationships is altered in breast cancer in humans. These findings highlight a role for the gut microbiome as a modulator, and thus a target, of interventions aiming at reducing breast cancer risk. They also provide foundational knowledge to explore the effects of early life interventions and mechanisms programming breast health.
... Through its association with different regulatory components, the endonuclease activity of DCR-1 can be directed to cleave pre-miRNAs and/or other double-stranded RNA substrates. These can then be further processed into the mature forms of miRNAs or siRNAs to execute their respective cellular tasks (Lee et al., 2013;Carthew & Sontheimer, 2009;Song & Rossi, 2017). The limited cellular abundance of DCR-1 may therefore contribute to competition among the pathways in certain physiological conditions, such that the active production of one class of DCR-1-dependent small RNAs proceeds at the expense of the production of the other classes (Zhuang & Hunter, 2012;Sawh & Duchaine, 2013). ...
It is well established that cells communicate with each other via signaling molecules and pathways. Recent work has further indicated that this transfer of information can breach the soma-to-germ line barrier, thus permitting changes in germline gene expression in response to cellular decisions made in somatic lineages. We show that during periods of extended energy stress AMPK alters small RNA biogenesis in somatic cells, which non-autonomously regulates the quiescence of germline stem cells. By combining both genetic analyses and a novel method of miRNA imaging, we show that AMPK-mediated phosphorylation acts as a molecular switch that drives the re-allocation of the key RNA endonuclease Dicer to the miRNA synthesis pathway during the dauer stage of C. elegans . By modifying Dicer and other components of the miRNA synthesis machinery, AMPK fine-tunes the production of a population of somatic miRNAs that act as a pro-quiescence signal to maintain germline integrity during periods of extended energy stress, thus bridging the gap between the soma and the germ line by altering small RNA homeostasis.
... Рибосома Dicer Drosha Таким образом, дерегуляция микроРНК имеет проонкогенный эффект: сверхэкспрессия одной микроРНК может ингибировать трансляцию белка гена -супрессора опухоли, в то время как подавление другой микроРНК может повышать уровень белка-онкогена [11][12][13]. В целом контроль экспрессии генов, опосредованных ми-кроРНК, имеет решающее значение для реакции клеток на окислительный стресс, гипоксию и повреждение ДНК. ...
DICER1 syndrome is a rare genetic disorder with the progressive development of malignant and non-malignant diseases in childhood. The cause of this syndrome is a dusfunction of the endoribonuclease DICER, which plays an important role in the processing of microRNAs with subsequent regulation of the control of the expression of oncogenes and tumor suppressor genes. Clinical manifestations of dyseropathies is very different and may include both endocrine manifestations – multinodular goiter, differentiated thyroid cancers, ovarian stromal tumors, pituitary blastoma, and non–endocrine formations — pleuropulmonary blastoma, cystic nephroma, pineoblastoma. The presence of somatic mutations of the DICER1 gene is a resultant stage in the pathogenesis of dyseropathies, determining the further path of oncogenesis. At present, DICER1 syndrome is diagnosed extremely rarely, which leads to late detection of the components of the disease in the patient, late diagnosis of neoplasms, lack of family counseling. Diagnosis at the early stages of the disease, the development of screening programs for the management of these patients allows minimizing the risks of developing more malignant, aggressive forms of the disease.
... RISC uses the guide RNA to find complementary mRNA sequences via Watson-Crick base pairing. When the complementary target-mRNA has hybridized with part of the guide strand, an endonucleolytic cleavage of the mRNA is driven by a component of RISC, the Argonaute 2 (Ago2) protein [23]. Because Ago2 is primarily localized to the cytoplasm, siRNAs effectively target cytoplasmic RNAs (Fig. 1). ...
Purpose of Review
Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with dyslipidemia do not achieve optimal management, and many of them are treated with low-intensity lipid-lowering therapies. Beyond the well-known association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular prevention, the atherogenicity of lipoprotein(a) and the impact of triglyceride (TG)-rich lipoproteins cannot be overlooked. Within this landscape, the use of RNA-based therapies can help the treatment of difficult to target lipid disorders.
Recent Findings
The safety and efficacy of LDL-C lowering with the siRNA inclisiran has been documented in the open-label ORION-3 trial, with a follow-up of 4 years. While the outcome trial is pending, a pooled analysis of ORION-9, ORION-10, and ORION-11 has shown the potential of inclisiran to reduce composite major adverse cardiovascular events. Concerning lipoprotein(a), data of OCEAN(a)-DOSE trial with olpasiran show a dose-dependent drop in lipoprotein(a) levels with an optimal pharmacodynamic profile when administered every 12 weeks. Concerning TG lowering, although ARO-APOC3 and ARO-ANG3 are effective to lower apolipoprotein(apo)C-III and angiopoietin-like 3 (ANGPTL3) levels, these drugs are still in their infancy.
Summary
In the era moving toward a personalized risk management, the use of siRNA represents a blossoming armamentarium to tackle dyslipidaemias for ASCVD risk reduction.
... However, until individual miRNAs are identified, we cannot eliminate the possibility that other functions of Dicer could also be important in regulating the expression of genes involved in Ca 2+ homeostasis in ESCs. Dicer can process other RNAs in the cell and affect the function of other proteins to which it forms a complex [40]. However, the mechanisms by which these other functions of Dicer could regulate gene expression are much less understood and, in other developmental systems that are affected by the deletion of Dicer, specific miRNAs have been found to be important for the phenotype. ...
MicroRNAs (miRNAs) are important regulators of embryonic stem cell (ESC) biology, and their study has identified key regulatory mechanisms. To find novel pathways regulated by miRNAs in ESCs, we undertook a bioinformatics analysis of gene pathways differently expressed in the absence of miRNAs due to the deletion of Dicer, which encodes an RNase that is essential for the synthesis of miRNAs. One pathway that stood out was Ca2+ signaling. Interestingly, we found that Dicer−/− ESCs had no difference in basal cytoplasmic Ca2+ levels but were hyperresponsive when Ca2+ import into the endoplasmic reticulum (ER) was blocked by thapsigargin. Remarkably, the increased Ca2+ response to thapsigargin in ESCs resulted in almost no increase in apoptosis and no differences in stress response pathways, despite the importance of miRNAs in the stress response of other cell types. The increased Ca2+ response in Dicer−/− ESCs was also observed during purinergic receptor activation, demonstrating a physiological role for the miRNA regulation of Ca2+ signaling pathways. In examining the mechanism of increased Ca2+ responsiveness to thapsigargin, neither store-operated Ca2+ entry nor Ca2+ clearance mechanisms from the cytoplasm appeared to be involved. Rather, it appeared to involve an increase in the expression of one isoform of the IP3 receptors (Itpr2). miRNA regulation of Itpr2 expression primarily appeared to be indirect, with transcriptional regulation playing a major role. Therefore, the miRNA regulation of Itpr2 expression offers a unique mechanism to regulate Ca2+ signaling pathways in the physiology of pluripotent stem cells.
