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.
In mammals, male germ cells differentiate from haploid round spermatids to flagella-containing motile sperm in a process called spermiogenesis. This process is distinct from somatic cell ...differentiation in that the majority of the core histones are replaced sequentially, first by transition proteins and then by protamines, facilitating chromatin hyper-compaction. This histone-to-protamine transition process represents an excellent model for the investigation of how epigenetic regulators interact with each other to remodel chromatin architecture. Although early work in the field highlighted the critical roles of testis-specific transcription factors in controlling the haploid-specific developmental program, recent studies underscore the essential functions of epigenetic players involved in the dramatic genome remodeling that takes place during wholesale histone replacement. In this review, we discuss recent advances in our understanding of how epigenetic players, such as histone variants and histone writers/readers/erasers, rewire the haploid spermatid genome to facilitate histone substitution by protamines in mammals.
Histone arginine methylation Di Lorenzo, Alessandra; Bedford, Mark T.
FEBS letters,
July 07, 2011, Letnik:
585, Številka:
13
Journal Article
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Arginine methylation is a common posttranslational modification (PTM). This type of PTM occurs on both nuclear and cytoplasmic proteins, and is particularly abundant on shuttling proteins. In this ...review, we will focus on one aspect of this PTM: the diverse roles that arginine methylation of the core histone tails play in regulating chromatin function. A family of nine protein arginine methyltransferases (PRMTs) catalyze methylation reactions, and a subset target histones. Importantly, arginine methylation of histone tails can promote or prevent the docking of key transcriptional effector molecules, thus playing a central role in the orchestration of the histone code.
Tudor domain-containing protein 3 (TDRD3) is a major methylarginine effector molecule that reads methyl-histone marks and facilitates gene transcription. However, the underlying mechanism by which ...TDRD3 functions as a transcriptional coactivator is unknown. We identified topoisomerase IIIB (TOP3B) as a component of the TDRD3 complex. TDRD3 serves as a molecular bridge between TOP3B and arginine-methylated histones. The TDRD3-TOP3B complex is recruited to the c-MYC gene promoter primarily by the H4R3me2a mark, and the complex promotes c-MYC gene expression. TOP3B relaxes negative supercoiled DNA and reduces transcription-generated R loops in vitro. TDRD3 knockdown in cells increases R loop formation at the c-MYC locus, and Tdrd3 null mice exhibit elevated R loop formation at this locus in B cells. Tdrd3 null mice show significantly increased c-Myc/Igh translocation, a process driven by R loop structures. By reducing negative supercoiling and resolving R loops, TOP3B promotes transcription, protects against DNA damage, and reduces the frequency of chromosomal translocations.
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•TDRD3 interacts with TOP3B to stabilize this methylarginine effector complex•The Tudor domain of TDRD3 facilitates the recruitment of this complex to chromatin•The TDRD3-TOP3B complex resolves R loops at the c-MYC locus•The absence of Tdrd3 results in increased c-Myc/Igh translocation in vivo
Yang et al. show that TDRD3 reads histone arginine methylation and recruits TOP3B to reduce R loops at transcription start sites. In particular, they find H4R3me2a-dependent recruitment of TDRD3-TOP3B to the c-MYC promoter. Furthermore, Tdrd3 null mice show increased R loop formation at the c-MYC locus and high rates of c-Myc/Igh translocations.
The type II arginine methyltransferase PRMT5 is responsible for the symmetric dimethylation of histone to generate the H3R8me2s and H4R3me2s marks, which correlate with the repression of ...transcription. However, the protein level of a number of genes (MEP50, CCND1, MYC, HIF1a, MTIF and CDKN1B) are reported to be downregulated by the loss of PRMT5, while their mRNA levels remain unchanged, which is counterintuitive for PRMT5's proposed role as a transcription repressor. We noticed that the majority of the genes regulated by PRMT5, at the posttranscriptional level, express mRNA containing an internal ribosome entry site (IRES). Using an IRES-dependent reporter system, we established that PRMT5 facilitates the translation of a subset of IRES-containing genes. The heterogeneous nuclear ribonucleoprotein, hnRNP A1, is an IRES transacting factor (ITAF) that regulates the IRES-dependent translation of Cyclin D1 and c-Myc. We showed that hnRNP A1 is methylated by PRMT5 on two residues, R218 and R225, and that this methylation facilitates the interaction of hnRNP A1 with IRES RNA to promote IRES-dependent translation. This study defines a new role for PRMT5 regulation of cellular protein levels, which goes beyond the known functions of PRMT5 as a transcription and splicing regulator.
The covalent marking of proteins by methyl group addition to arginine residues can promote their recognition by binding partners or can modulate their biological activity. A small family of gene ...products that catalyze such methylation reactions in eukaryotes (PRMTs) works in conjunction with a changing cast of associated subunits to recognize distinct cellular substrates. These reactions display many of the attributes of reversible covalent modifications such as protein phosphorylation or protein lysine methylation; however, it is unclear to what extent protein arginine demethylation occurs. Physiological roles for protein arginine methylation have been established in signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation.
Readers of histone methylarginine marks Gayatri, Sitaram; Bedford, Mark T.
Biochimica et biophysica acta,
08/2014, Letnik:
1839, Številka:
8
Journal Article
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Arginine methylation is a common posttranslational modification (PTM) that alters roughly 0.5% of all arginine residues in the cells. There are three types of arginine methylation: monomethylarginine ...(MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). These three PTMs are enriched on RNA-binding proteins and on histones, and also impact signal transduction cascades. To date, over thirty arginine methylation sites have been cataloged on the different core histones. These modifications alter protein structure, impact interactions with DNA, and also generate docking sites for effector molecules. The primary “readers” of methylarginine marks are Tudor domain-containing proteins. The complete family of thirty-six Tudor domain-containing proteins has yet to be fully characterized, but at least ten bind methyllysine motifs and eight bind methylarginine motifs. In this review, we will highlight the biological roles of the Tudor domains that interact with arginine methylated motifs, and also address other types of interactions that are regulated by these particular PTMs. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function.
•0.5% of all arginine residues in the cell are methylated.•There are three types of arginine methylation: mono, asymmetric & symmetric.•The primary “readers” of methylarginine marks are Tudor domain-containing proteins.
Arginine methylation is a ubiquitous and relatively stable post-translational modification (PTM) that occurs in three types: monomethylarginine (MMA), asymmetric dimethylarginine (ADMA) and symmetric ...dimethylarginine (SDMA). Methylarginine marks are catalyzed by members of the protein arginine methyltransferases (PRMTs) family of enzymes. Substrates for arginine methylation are found in most cellular compartments, with RNA-binding proteins forming the majority of PRMT targets. Arginine methylation often occurs in intrinsically disordered regions of proteins, which impacts biological processes like protein-protein interactions and phase separation, to modulate gene transcription, mRNA splicing and signal transduction. With regards to protein-protein interactions, the major 'readers' of methylarginine marks are Tudor domain-containing proteins, although additional domain types and unique protein folds have also recently been identified as methylarginine readers. Here, we will assess the current 'state-of-the-art' in the arginine methylation reader field. We will focus on the biological functions of the Tudor domain-containing methylarginine readers and address other domains and complexes that sense methylarginine marks.
In skeletal muscle, asymmetrically dividing satellite stem cells give rise to committed satellite cells that transcribe the myogenic determination factor Myf5, a Pax7-target gene. We identified the ...arginine methyltransferase Carm1 as a Pax7 interacting protein and found that Carm1 specifically methylates multiple arginines in the N terminus of Pax7. Methylated Pax7 directly binds the C-terminal cleavage forms of the trithorax proteins MLL1/2 resulting in the recruitment of the ASH2L:MLL1/2:WDR5:RBBP5 histone H3K4 methyltransferase complex to regulatory enhancers and the proximal promoter of Myf5. Finally, Carm1 is required for the induction of de novo Myf5 transcription following asymmetric satellite stem cell divisions. We defined the C-terminal MLL region as a reader domain for the recognition of arginine methylated proteins such as Pax7. Thus, arginine methylation of Pax7 by Carm1 functions as a molecular switch controlling the epigenetic induction of Myf5 during satellite stem cell asymmetric division and entry into the myogenic program.
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► Carm1 methylates Pax7 at specific arginines within the N-terminus ► Methylated Pax7 directly binds to C-terminal cleavage forms of MLL1/2 ► Methylated Pax7 recruits ASH2L:MLL1/2:WDR5:RBBP5 H3K4 methyltransferase complex ► Pax7-Carm1 is required for Myf5 expression following asymmetric stem cell division
A regulatory mechanism for Pax7 activity in satellite cells and myogenic differentiation of daughter cells involving arginine methylation by Carm1 and then binding of the MLL1/2 histone methyltransferase complex.
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