PIWI-interacting RNAs: small RNAs with big functions

Özata, Deniz M.; Gainetdinov, Ildar; Zoch, Ansgar; O’Carroll, Dónal; Zamore, Phillip D.

doi:10.1038/s41576-018-0073-3

Cited by 920 publications

(1,037 citation statements)

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“…piRNAs are small non-coding RNAs enriched in the germline. piRNAs assemble the piRNA-induced silencing complexes (piRISCs) with members of the PIWI family of proteins [13][14][15][16]. piRNAs show high complementarity to transposon RNA transcripts in both sense and antisense orientations and repress transposons transcriptionally, by inducing local heterochromatinization, or post-transcriptionally, by cleaving target RNAs [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

“…piRNAs assemble the piRNA-induced silencing complexes (piRISCs) with members of the PIWI family of proteins [13][14][15][16]. piRNAs show high complementarity to transposon RNA transcripts in both sense and antisense orientations and repress transposons transcriptionally, by inducing local heterochromatinization, or post-transcriptionally, by cleaving target RNAs [13][14][15][16]. In Drosophila ovarian somatic cells (OSCs), piRNAs assemble piRISCs solely with Piwi, the only nuclear member of the PIWI protein family, and, with multiple co-factors, transcriptionally repress transposons [12,[17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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Essential roles of Windei and nuclear monoubiquitination of Eggless/ SETDB 1 in transposon silencing

et al. 2019

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Eggless/SETDB1 (Egg), the only essential histone methyltransferase (HMT) in Drosophila, plays a role in gene repression, including piRNA‐mediated transposon silencing in the ovaries. Previous studies suggested that Egg is post‐translationally modified and showed that Windei (Wde) regulates Egg nuclear localization through protein–protein interaction. Monoubiquitination of mammalian SETDB1 is necessary for the HMT activity. Here, using cultured ovarian somatic cells, we show that Egg is monoubiquitinated and phosphorylated but that only monoubiquitination is required for piRNA‐mediated transposon repression. Egg monoubiquitination occurs in the nucleus. Egg has its own nuclear localization signal, and the nuclear import of Egg is Wde‐independent. Wde recruits Egg to the chromatin at target gene silencing loci, but their interaction is monoubiquitin‐independent. The abundance of nuclear Egg is governed by that of nuclear Wde. These results illuminate essential roles of nuclear monoubiquitination of Egg and the role of Wde in piRNA‐mediated transposon repression.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Essential roles of Windei and nuclear monoubiquitination of Eggless/ SETDB 1 in transposon silencing

et al. 2019

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“…Microsatellite diseases are a class of neurological and neuromuscular disorders caused by repeat expansions. 129 These expansions can be located in (1) open reading frames (Huntington's disease, HD), (2) untranslated regions (myotonic muscular dystrophy type 1, DM1; fragile X-associated tremor ataxia syndrome, FXTAS; and fragile X syndrome, FXS), and (3) introns (amyotrophic lateral sclerosis, ALS; and myotonic dystrophy type 2, DM2) ( Fig. 3B).…”

Section: Rna Expansion Elementsmentioning

confidence: 99%

“…Recent advances in the field of RNA biology has led to the discovery of a plethora of coding and non-coding (nc) transcripts with novel modes of action, 1 new types of RNA epitranscriptomic modifications, 2,3 and an unforeseen diversity of mechanisms that lead to the production of RNAs. 4 These discoveries prompted the parallel development of modern molecular techniques that provide in-depth insights to the RNA structure and function.…”

Section: Introductionmentioning

confidence: 99%

Unveiling the druggable RNA targets and small molecule therapeutics

Sztuba-Solińska

Chávez-Calvillo

Cline

2019

Bioorganic & Medicinal Chemistry

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Keywords:RNA structure and function RNA interactions Epitranscriptomics Small molecules RNA-based therapeutics RNA in disease Drug target A B S T R A C T The increasing appreciation for the crucial roles of RNAs in infectious and non-infectious human diseases makes them attractive therapeutic targets. Coding and non-coding RNAs frequently fold into complex conformations which, if effectively targeted, offer opportunities to therapeutically modulate numerous cellular processes, including those linked to undruggable protein targets. Despite the considerable skepticism as to whether RNAs can be targeted with small molecule therapeutics, overwhelming evidence suggests the challenges we are currently facing are not outside the realm of possibility. In this review, we highlight the most recent advances in molecular techniques that have sparked a revolution in understanding the RNA structure-to-function relationship. We bring attention to the application of these modern techniques to identify druggable RNA targets and to assess small molecule binding specificity. Finally, we discuss novel screening methodologies that support RNA drug discovery and present examples of therapeutically valuable RNA targets. RNA as a drug targetThe vast diversity of RNAs expanding beyond coding transcripts to several classes of ncRNAs that vary in length, biogenesis, polarity, and putative functions, increases the repertoire of druggable targets. 19,20 Here, specific RNA properties contribute to its attractive, yet challenging makeup as a target molecule. RNA can form complex three-dimensional structures through canonical Watson-Crick base pairing and complex tertiary interactions that are mediated by non-canonical bonds. Such structures can be as intricate and stable as those formed by proteins and can recognize small-molecule ligands, other nucleic acids, and/or proteins with high affinity and specificity. [21][22][23][24] At the same time, the highly dynamic conformation and repetitive character of its surface presents difficulties for drug design. 25,26 In addition, many putative small molecule-binding pockets in RNA are much more polar and solvent exposed than binding sites on proteins, complicating ligand design efforts. Compounding these issues, most target RNAs are expressed at low levels, with the exception of ribosomal (rRNA) and transfer (tRNA) RNAs, which constitute 80-90% and 10-15% of total cellular RNA, respectively. 27 Other abundant RNAs, such as messenger (mRNA), small nuclear (snRNA), and small nucleolar (snoRNA) are present at levels that are about 1-2 orders of magnitude lower than rRNA and tRNA. Certain small RNAs, such as micro (miRNA) and piwi (piRNAs) can be present at very high levels; however, this appears to be cell type dependent. One should keep in mind that if the RNA has catalytic activity or if it acts as a scaffold to regulate https://doi.

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“…More and more evidence reveals that noncoding RNAs (ncRNAs) account majority (98.2%) of human RNAs and play critical roles in regulating gene expression at the transcriptional, translational, and posttranslational levels, though they are not translated into proteins. 9 In particular, microRNA (miRNA) containing 22 nucleotides is one type of ncRNA and profiling miRNA expression is of widespread interest because of their critical roles in diverse biological processes, including development, cell proliferation, differentiation, and apoptosis of cancer cells. 10,11 Certain miR-NAs can serve as indicators of the poor survival of patients with cancer.…”

Section: Introductionmentioning

confidence: 99%

Integrating high‐throughput microRNA and mRNA expression data to identify risk mRNA signature for pancreatic cancer prognosis

Wang

Zhai

et al. 2019

J of Cellular Biochemistry

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Pancreatic cancer is a malignancy of the digestive system characterized by poor prognosis. A number of prognostic messenger RNA (mRNA) signatures have been identified by using the high-throughput expression profiles. MicroRNAs (miRNA) play a critical role in regulating multiple cellular functions. However, no such integrated analysis of miRNAs and mRNAs for studying the prognostic mechanisms of pancreatic cancer has been reported. In this study, we first identified prognostic mRNAs and miRNAs based on The Cancer Genome Atlas datasets, and then performed an enrichment analysis to explore the underlying

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PIWI-interacting RNAs: small RNAs with big functions

Cited by 920 publications

References 321 publications

Essential roles of Windei and nuclear monoubiquitination of Eggless/ SETDB 1 in transposon silencing

Essential roles of Windei and nuclear monoubiquitination of Eggless/ SETDB 1 in transposon silencing

Unveiling the druggable RNA targets and small molecule therapeutics

Integrating high‐throughput microRNA and mRNA expression data to identify risk mRNA signature for pancreatic cancer prognosis

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