The MID-PIWI module of Piwi proteins specifies nucleotide- and strand-biases of piRNAs

Cora, Elisa; Pandey, Radha Raman; Xiol, Jordi; Taylor, Josh; Sachidanandam, Ravi; McCarthy, A.A.; Pillai, Ramesh S.

doi:10.1261/rna.044701.114

Cited by 80 publications

(78 citation statements)

References 44 publications

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“…In the case of Ago silencing via non-slicer mechanisms, GW182-family proteins, named for their enrichment in glycine and tryptophan residues, are recruited to RISC (reviewed in [105]) through interactions with the PIWI domain [91,95] (Fig. 2a).…”

Section: Hhmi Author Manuscriptmentioning

confidence: 99%

“…Our current understanding of the molecular mechanisms of Piwi proteins is primarily based on numerous genetic screens, biochemical assays, and comparisons to their Ago counterparts. The existing structural data on eukaryotic Piwis focuses on individual domains, specifically the 3′-binding PAZ domain and 5′-binding MID domain [105,106], both of which show extensive interactions with the ends of the RNA guide. As is the case for Ago, the 5′ phosphate is bound tightly by the MID-PIWI lobe and the identity of the 5′ nucleotide is "read" by the nucleotide specificity loop [105].…”

Section: Hhmi Author Manuscriptmentioning

confidence: 99%

“…The existing structural data on eukaryotic Piwis focuses on individual domains, specifically the 3′-binding PAZ domain and 5′-binding MID domain [105,106], both of which show extensive interactions with the ends of the RNA guide. As is the case for Ago, the 5′ phosphate is bound tightly by the MID-PIWI lobe and the identity of the 5′ nucleotide is "read" by the nucleotide specificity loop [105]. Also similar to Agos, the opposite end of the guide RNA is recognized by the PAZ domain.…”

Section: Hhmi Author Manuscriptmentioning

confidence: 99%

“…Subsequent conformational changes allow for validation of the target using nucleotides 6-7, followed by nucleotides 8 and/or 13-16 [93]. Additional structures are still needed, however, to better explain the atomic underpinnings of slicing and product ejection as the formation of more extended duplexes will require additional conformational rearrangements.In the case of Ago silencing via non-slicer mechanisms, GW182-family proteins, named for their enrichment in glycine and tryptophan residues, are recruited to RISC (reviewed in [105]) through interactions with the PIWI domain [91,95] (Fig. 2a).…”

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

Ipsaro

Joshua‐Tor

2015

Nat Struct Mol Biol

216

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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Section: Hhmi Author Manuscriptmentioning

confidence: 99%

Section: Hhmi Author Manuscriptmentioning

confidence: 99%

Section: Hhmi Author Manuscriptmentioning

confidence: 99%

mentioning

confidence: 99%

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

Ipsaro

Joshua‐Tor

2015

Nat Struct Mol Biol

216

144

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“…We first checked for typical piRNA features like the 1U bias that results from 5 ′ Uridine recognition of Piwi proteins (Cora et al 2014). We found that the 26-34 nt fraction, but not the 18-25 nt fraction exhibits a strong bias for Uridine at position 1 (Fig.…”

Section: Identification Of Pirnasmentioning

confidence: 99%

Tupaia small RNAs provide insights into function and evolution of RNAi-based transposon defense in mammals

Rosenkranz

Rudloff

Bastuck

et al. 2015

RNA

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Argonaute proteins comprising Piwi-like and Argonaute-like proteins and their guiding small RNAs combat mobile DNA on the transcriptional and post-transcriptional level. While Piwi-like proteins and associated piRNAs are generally restricted to the germline, Argonaute-like proteins and siRNAs have been linked with transposon control in the germline as well as in the soma. Intriguingly, evolution has realized distinct Argonaute subfunctionalization patterns in different species but our knowledge about mammalian RNA interference pathways relies mainly on findings from the mouse model. However, mice differ from other mammals by absence of functional Piwil3 and expression of an oocyte-specific Dicer isoform. Thus, studies beyond the mouse model are required for a thorough understanding of function and evolution of mammalian RNA interference pathways. We high-throughput sequenced small RNAs from the male Tupaia belangeri germline, which represents a close outgroup to primates, hence phylogenetically links mice with humans. We identified transposon-derived piRNAs as well as siRNAs clearly contrasting the separation of piRNA-and siRNA-pathways into male and female germline as seen in mice. Genome-wide analysis of tree shrew transposons reveal that putative siRNAs map to transposon sites that form foldback secondary structures thus representing suitable Dicer substrates. In contrast piRNAs target transposon sites that remain accessible. With this we provide a basic mechanistic explanation how secondary structure of transposon transcripts influences piRNA-and siRNApathway utilization. Finally, our analyses of tree shrew piRNA clusters indicate A-Myb and the testis-expressed transcription factor RFX4 to be involved in the transcriptional regulation of mammalian piRNA clusters.

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Investigating piwi‐interacting RNA regulome in human neuroblastoma

Roy

Mallick

2018

Genes Chromosomes & Cancer

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Remarkable attempts have been exercised in recent years using high-throughput technologies to identify and decipher the functions of piRNAs in various abnormalities like cancer. However, piRNAs in the oncogenesis of neuroblastoma (NB) has not been reported yet even after their illustrated roles in neurological processes. Therefore, we investigated the piRNA transcriptome in IMR-32 and SH-SY-5Y NB cell lines by employing high-throughput next-generation sequencing after confirming the expression of three associated PIWILs both at mRNAs and protein level by qRT-PCR and immunofluroscence, respectively. We identified a common pool of 525 piRNAs of 26-32 nts long expressed in both the cell lines. The possible functions of these piRNAs were charted by predicting their targeting on retrotransposon-containing 1769 mRNAs differentially expressed in 39 NB cell lines followed by network and pathway analysis. The analysis revealed that majority of the target binding sites in NB fall within retrotransposons residing within the 3'UTR of target mRNA transcripts like miRNA-targets. Further, we validated the expression of key piRNAs and their target genes enriched in cancer-related networks, pathways and biological processes which are hypothesized to play crucial roles in neoplastic events of NB. We believe that the evidence of piRNAs in human NB and their possible contribution to its pathogenesis reported in this work will open up new exciting possibilities for piRNA-mediated therapeutics for this malignancy.

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The MID-PIWI module of Piwi proteins specifies nucleotide- and strand-biases of piRNAs

Cited by 80 publications

References 44 publications

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

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

Tupaia small RNAs provide insights into function and evolution of RNAi-based transposon defense in mammals

Investigating piwi‐interacting RNA regulome in human neuroblastoma

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