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Journal ArticleDOI

Deciphering arginine methylation: Tudor tells the tale

01 Oct 2011-Nature Reviews Molecular Cell Biology (Nature Publishing Group)-Vol. 12, Iss: 10, pp 629-642
TL;DR: Tudor proteins are now known to be present in PIWI complexes, where they are thought to interact with methylated PIWI proteins and regulate the PIWI-interacting RNA (piRNA) pathway in the germ line.
Abstract: Proteins can be modified by post-translational modifications such as phosphorylation, methylation, acetylation and ubiquitylation, creating binding sites for specific protein domains. Methylation has pivotal roles in the formation of complexes that are involved in cellular regulation, including in the generation of small RNAs. Arginine methylation was discovered half a century ago, but the ability of methylarginine sites to serve as binding motifs for members of the Tudor protein family, and the functional significance of the protein-protein interactions that are mediated by Tudor domains, has only recently been appreciated. Tudor proteins are now known to be present in PIWI complexes, where they are thought to interact with methylated PIWI proteins and regulate the PIWI-interacting RNA (piRNA) pathway in the germ line.
Citations
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Journal ArticleDOI
TL;DR: It is demonstrated that the disordered tails of Ddx4, a primary constituent of nuage or germ granules, form phase-separated organelles both in live cells and in vitro, and proposed that phase separation of disordered proteins containing weakly interacting blocks is a general mechanism for forming regulated, membraneless organlles.

1,307 citations


Cites background from "Deciphering arginine methylation: T..."

  • ...by small perturbations, for example by methylation of arginines by PRMT1, a modification observed in vivo (Chen et al., 2011)....

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Journal ArticleDOI
TL;DR: Genetic and functional evidence suggests that hyperactivation of this pathway is a driver of oncogenesis and establishes a link to cellular epigenetic status, which could present opportunities for translation into precision cancer medicine.
Abstract: One-carbon metabolism involving the folate and methionine cycles integrates nutritional status from amino acids, glucose and vitamins, and generates diverse outputs, such as the biosynthesis of lipids, nucleotides and proteins, the maintenance of redox status and the substrates for methylation reactions. Long considered a 'housekeeping' process, this pathway has recently been shown to have additional complexity. Genetic and functional evidence suggests that hyperactivation of this pathway is a driver of oncogenesis and establishes a link to cellular epigenetic status. Given the wealth of clinically available agents that target one-carbon metabolism, these new findings could present opportunities for translation into precision cancer medicine.

1,190 citations

Journal ArticleDOI
TL;DR: There are nine protein arginine methyltransferases (PRMTs) encoded in mammalian genomes, the protein products of which catalyse three types of ARG modifications: monomethylation and two types of dimethylation as discussed by the authors.
Abstract: There are nine protein arginine methyltransferases (PRMTs) encoded in mammalian genomes, the protein products of which catalyse three types of arginine methylation--monomethylation and two types of dimethylation. Protein arginine methylation is an abundant modification that has been implicated in signal transduction, gene transcription, DNA repair and mRNA splicing, among others. Studies have only recently linked this modification to carcinogenesis and metastasis. Sequencing studies have not generally found alterations to the PRMTs; however, overexpression of these enzymes is often associated with various cancers, which might make some of them viable targets for therapeutic strategies.

853 citations

Journal ArticleDOI
TL;DR: The latest advances in characterizing histone-binding mechanisms and identifying new epigenetic readers are highlighted and the functional significance of PTM recognition is summarized.
Abstract: Post-translational modifications (PTMs) of histones provide a fine-tuned mechanism for regulating chromatin structure and dynamics. PTMs can alter direct interactions between histones and DNA and serve as docking sites for protein effectors, or readers, of these PTMs. Binding of the readers recruits or stabilizes various components of the nuclear signaling machinery at specific genomic sites, mediating fundamental DNA-templated processes, including gene transcription and DNA recombination, replication and repair. In this review, we highlight the latest advances in characterizing histone-binding mechanisms and identifying new epigenetic readers and summarize the functional significance of PTM recognition.

719 citations

Journal ArticleDOI
TL;DR: The authors describe the latest understanding of piRNA biogenesis and functions across diverse species, highlighting how, despite the universal importance of transposon control, different species have evolved intriguingly distinct mechanistic routes to achieve this.
Abstract: In animals, PIWI-interacting RNAs (piRNAs) of 21–35 nucleotides in length silence transposable elements, regulate gene expression and fight viral infection. piRNAs guide PIWI proteins to cleave target RNA, promote heterochromatin assembly and methylate DNA. The architecture of the piRNA pathway allows it both to provide adaptive, sequence-based immunity to rapidly evolving viruses and transposons and to regulate conserved host genes. piRNAs silence transposons in the germ line of most animals, whereas somatic piRNA functions have been lost, gained and lost again across evolution. Moreover, most piRNA pathway proteins are deeply conserved, but different animals employ remarkably divergent strategies to produce piRNA precursor transcripts. Here, we discuss how a common piRNA pathway allows animals to recognize diverse targets, ranging from selfish genetic elements to genes essential for gametogenesis. PIWI-interacting RNAs (piRNAs) have numerous crucial biological roles, particularly transposon silencing in the germ line. In this Review, the authors describe our latest understanding of piRNA biogenesis and functions across diverse species, highlighting how, despite the universal importance of transposon control, different species have evolved intriguingly distinct mechanistic routes to achieve this.

686 citations

References
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Journal ArticleDOI
TL;DR: This Review summarizes the current knowledge of how these intriguing molecules are generated in animal cells.
Abstract: Small RNAs of 20-30 nucleotides can target both chromatin and transcripts, and thereby keep both the genome and the transcriptome under extensive surveillance. Recent progress in high-throughput sequencing has uncovered an astounding landscape of small RNAs in eukaryotic cells. Various small RNAs of distinctive characteristics have been found and can be classified into three classes based on their biogenesis mechanism and the type of Argonaute protein that they are associated with: microRNAs (miRNAs), endogenous small interfering RNAs (endo-siRNAs or esiRNAs) and Piwi-interacting RNAs (piRNAs). This Review summarizes our current knowledge of how these intriguing molecules are generated in animal cells.

3,081 citations

Journal ArticleDOI
23 Mar 2007-Cell
TL;DR: Examination of piwi-interacting RNAs associated with each Drosophila Piwi protein finds that Piwi and Aubergine bind RNAs that are predominantly antisense to transposons, whereas Ago3 complexes contain predominantly sense piRNAs.

2,303 citations

Journal ArticleDOI
19 Dec 1997-Science
TL;DR: The role of scaffold, anchoring, and adaptor proteins that contribute to the specificity of signal transduction events by recruiting active enzymes into signaling networks or by placing enzymes close to their substrates is discussed.
Abstract: The process by which extracellular signals are relayed from the plasma membrane to specific intracellular sites is an essential facet of cellular regulation. Many signaling pathways do so by altering the phosphorylation state of tyrosine, serine, or threonine residues of target proteins. Recently, it has become apparent that regulatory mechanisms exist to influence where and when protein kinases and phosphatases are activated in the cell. The role of scaffold, anchoring, and adaptor proteins that contribute to the specificity of signal transduction events by recruiting active enzymes into signaling networks or by placing enzymes close to their substrates is discussed.

2,237 citations

Journal ArticleDOI
13 Jul 2006-Nature
TL;DR: It is shown that MIWI, a murine Piwi protein, binds a previously uncharacterized class of ∼29–30-nucleotide RNAs that are highly abundant in testes and are named Piwi-interacting RNAs (piRNAs), suggesting a role in gametogenesis.
Abstract: In RNA interference, small RNAs (siRNAs or miRNAs) act to regulate gene expression. They serve as specificity factors that direct the RISC (RNA-induced silencing) complex to the complementary mRNA targets. A major component of RISC is a protein of the Argonaute family. Two groups have now identified a new class of small RNAs that interact with one Argonaute subfamily, the Piwi class. These testis-specific small RNAs, called 'piRNAs', are slightly longer than the previously described small RNAs. The function of the piRNAs is not yet known, but they might be involved in sperm production. One of two studies that identifies a new class of small RNAs that interact with one Argonaute subfamily, the Piwi class. These testis-specific small RNAs, called 'piRNAs', are slightly longer than the previously described siRNAs and miRNAs. Small RNAs associate with Argonaute proteins and serve as sequence-specific guides to regulate messenger RNA stability, protein synthesis, chromatin organization and genome structure1,2,3. In animals, Argonaute proteins segregate into two subfamilies4. The Argonaute subfamily acts in RNA interference and in microRNA-mediated gene regulation using 21–22-nucleotide RNAs as guides. The Piwi subfamily is involved in germline-specific events such as germline stem cell maintenance and meiosis. However, neither the biochemical function of Piwi proteins nor the nature of their small RNA guides is known. Here we show that MIWI, a murine Piwi protein, binds a previously uncharacterized class of ∼29–30-nucleotide RNAs that are highly abundant in testes. We have therefore named these Piwi-interacting RNAs (piRNAs). piRNAs show distinctive localization patterns in the genome, being predominantly grouped into 20–90-kilobase clusters, wherein long stretches of small RNAs are derived from only one strand. Similar piRNAs are also found in human and rat, with major clusters occurring in syntenic locations. Although their function must still be resolved, the abundance of piRNAs in germline cells and the male sterility of Miwi mutants suggest a role in gametogenesis.

1,590 citations

Journal ArticleDOI
TL;DR: Physiological roles for protein arginine methylation have been established in signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation.

1,525 citations