Argonaute proteins: functional insights and emerging roles

Meister, Gunter

doi:10.1038/nrg3462

Cited by 914 publications

(827 citation statements)

References 172 publications

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“…In the post-prandial state, as extracellular glucose concentrations subside within hours, it is not clear whether these transcripts encoding secretion-mediating genes are quickly degraded or rather stabilized in preparation for subsequent metabolic signals. Therefore, one possible function for miRNAs may be to bind these mRNAs in a sequence specific manner with the assistance of RNA-binding proteins (i.e Argonautes) in order to protect and delay degradation over the course of several hours [30] [31]. In the event that extracellular glucose levels again arise within an acute time frame, the miRNAs can then be 'de-recruited' from these transcripts to facilitate expression of the proteins regulating the breakdown of glucose and insulin release.…”

Section: Identification Of Microrna Targets In the β-Cellmentioning

confidence: 99%

MicroRNAs: An adaptive mechanism in the pancreatic β-cell…and beyond?

Poy

2016

Best Practice & Research Clinical Endocrinology & Metab

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Recent protocols have been developed to differentiate human stem cells and fibroblasts into insulin-producing cells capable of releasing the hormone in a glucosestimulated manner. Limitations remain which prevent bringing these protocols to a clinical setting as these models must still undergo complete characterization. Advances in sequencing technologies have driven the identification of several noncoding RNA species including microRNAs (miRNAs). While their diversity and unique expression patterns across different tissues have made deciphering their precise functional role a significant challenge, studies using both cell lines and transgenic mouse models have made substantial progress in understanding their regulatory role on exocytosis and proliferation of the β-cell. These results also indicate miRNAs play an integral role in the fundamental mechanics of how the cell manages the balance between these independent functions. Continued investigation into miRNA function may uncover mechanisms which can be exploited to improve differentiation protocols in producing fully mature β-cells.

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Section: Identification Of Microrna Targets In the β-Cellmentioning

confidence: 99%

MicroRNAs: An adaptive mechanism in the pancreatic β-cell…and beyond?

Poy

2016

Best Practice & Research Clinical Endocrinology & Metab

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“…2 MiRNA undergo a complex biosynthetic process starting in the nucleus where the Drosha-Pasha microprocessor complex effects the first cleavage, transforming primary transcripts, or pri-miRNA, into pre-miRNA. 3 Pre-miRNA is then exported to the cytoplasm where Dicer performs the second cleavage, generating mature miRNA. 3 The miRNA is then integrated into an RNA-induced silencing complex (RISC), which guides recognition of a complementary sequence of mRNA.…”

Section: Introductionmentioning

confidence: 99%

“…3 Pre-miRNA is then exported to the cytoplasm where Dicer performs the second cleavage, generating mature miRNA. 3 The miRNA is then integrated into an RNA-induced silencing complex (RISC), which guides recognition of a complementary sequence of mRNA. Argonaute proteins (AGO1-4), which constitute the catalytic component of the RISC, cleave the mRNA, effectively blocking translation.…”

Section: Introductionmentioning

confidence: 99%

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Five children with deletions of 1p34.3 encompassing AGO1 and AGO3

et al. 2014

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Small RNAs (miRNA, siRNA, and piRNA) regulate gene expression through targeted destruction or translational repression of specific messenger RNA in a fundamental biological process called RNA interference (RNAi). The Argonaute proteins, which derive from a highly conserved family of genes found in almost all eukaryotes, are critical mediators of this process. Four AGO genes are present in humans, three of which (AGO 1, 3, and 4) reside in a cluster on chromosome 1p35p34. The effects of germline AGO variants or dosage alterations in humans are not known, however, prior studies have implicated dysregulation of the RNAi mechanism in the pathogenesis of several neurodevelopmental disorders. We describe five patients with hypotonia, poor feeding, and developmental delay who were found to have microdeletions of chromosomal region 1p34.3 encompassing the AGO1 and AGO3 genes. We postulate that haploinsufficiency of AGO1 and AGO3 leading to impaired RNAi may be responsible for the neurocognitive deficits present in these patients. However, additional studies with rigorous phenotypic characterization of larger cohorts of affected individuals and systematic investigation of the underlying molecular defects will be necessary to confirm this.

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“…When loaded with a single-stranded guide RNA, Argonautes form functional RISCs, which can be directed to their target by base pairing interactions and impart silencing through a variety of direct or indirect mechanisms (reviewed in [61,62]). Currently, this family is broken down into three clades in animals, each with slightly different properties: Ago, Piwi, and Wago (worm-specific Argonautes) [63].…”

Section: Rnai Effector Machinerymentioning

confidence: 99%

From guide to target: molecular insights into eukaryotic RNA-interference machinery

Ipsaro

Joshua‐Tor

2015

Nat Struct Mol Biol

218

144

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Since its relatively recent discovery, RNA interference (RNAi) has emerged as a potent, specific, and ubiquitous means of gene regulation. Through a number of pathways that are conserved from yeast to humans, small non-coding RNAs direct molecular machinery to silence gene expression. In this review, we focus on mechanisms and structures that govern RNA silencing in higher organisms. In addition to highlighting recent advances, parallels and differences between RNAi pathways are discussed. Together, the studies reviewed herein reveal the versatility and programmability of RNA-induced Silencing Complexes (RISCs) and emphasize the importance of both upstream biogenesis and downstream silencing factors. Discovery and Biological Perspectives of RNA interferenceRNAi was first described by Fire and Mello in the 1990s when, in an attempt to use antisense RNA to down-regulate gene expression, they observed that double-stranded RNA (dsRNA) was more potent than sense or anti-sense RNA alone [1]. This seminal work boasted robust and specific gene knock down in addition to coining the term "RNA interference" (RNAi). Shortly beforehand, the discovery of individual regulatory RNAs in C. elegans hinted that small, non-coding RNAs might be a pervasive means of gene regulation in higher organisms [2,3]. In the following decade, with the mechanistic insight of Fire and Mello's work in hand, this idea was confirmed and it is now accepted that wellover 1,000 small RNAs are encoded in the human genome that may regulate over 60% of our genes [4,5]. It also became apparent that several seemingly disconnected phenomena are variations of RNAi-type pathways including co-suppression in plants, DNA elimination in Tetrahymena, and quelling in Neurospora [6]. The prevalence of RNAi is impressive and its importance is underscored by the fact that RNAi dysfunction is associated with numerous diseases and disorders including neurological maladies, cancers, and infertility.Shortly after the initial description of RNAi phenomenology, a burst of genetic, biochemical, biophysical, and bioinformatic efforts laid a strong foundation for identifying the molecular pathways, players, and parameters that govern silencing via RNAi. Work from Reprints and permissions information is available online at http://www.nature.com/reprints/index.html. HHMI Author ManuscriptHHMI Author Manuscript HHMI Author Manuscript numerous groups defined the molecular apparatus of RNAi as RISC (RNA-induced Silencing Complex), a ribonucleoprotein complex minimally comprised of a small singlestranded RNA (~20-31 nucleotides) and an Argonaute protein which serves as the effector molecule (reviewed in [7]). In this configuration, the loaded "guide" RNA acts as a specificity determinant that directs Argonaute and any other associated machinery to the target. The guide-loaded Argonaute platform underlies every example in the expansive array of known RNAi pathways in eukaryotes regardless of the source of the guide (structured loci, transposons, viral, etc.), the machinery ...

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Argonaute proteins: functional insights and emerging roles

Cited by 914 publications

References 172 publications

MicroRNAs: An adaptive mechanism in the pancreatic β-cell…and beyond?

MicroRNAs: An adaptive mechanism in the pancreatic β-cell…and beyond?

Five children with deletions of 1p34.3 encompassing AGO1 and AGO3

From guide to target: molecular insights into eukaryotic RNA-interference machinery

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