The Experts below are selected from a list of 1683 Experts worldwide ranked by ideXlab platform
Mark T Bedford - One of the best experts on this subject based on the ideXlab platform.
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the role of the prmt5 snd1 axis in hepatocellular carcinoma
Epigenomes, 2021Co-Authors: Tanner Wright, Yalong Wang, Mark T BedfordAbstract:Arginine methylation is an essential post-translational modification (PTM) deposited by protein arginine methyltransferases (PRMTs) and recognized by Tudor Domain-containing proteins. Of the nine mammalian PRMTs, PRMT5 is the primary enzyme responsible for the deposition of symmetric arginine methylation marks in cells. The staphylococcal nuclease and Tudor Domain-containing 1 (SND1) effector protein is a key reader of the marks deposited by PRMT5. Both PRMT5 and SND1 are broadly expressed and their deregulation is reported to be associated with a range of disease phenotypes, including cancer. Hepatocellular carcinoma (HCC) is an example of a cancer type that often displays elevated PRMT5 and SND1 levels, and there is evidence that hyperactivation of this axis is oncogenic. Importantly, this pathway can be tempered with small-molecule inhibitors that target PRMT5, offering a therapeutic node for cancer, such as HCC, that display high PRMT5–SND1 axis activity. Here we summarize the known activities of this writer–reader pair, with a focus on their biological roles in HCC. This will help establish a foundation for treating HCC with PRMT5 inhibitors and also identify potential biomarkers that could predict sensitivity to this type of therapy.
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g9a mediated methylation of erα links the phf20 mof histone acetyltransferase complex to hormonal gene expression
Nature Communications, 2016Co-Authors: Xi Zhang, Mark T Bedford, Cari A Sagum, Danni Peng, Chao Yuan, Brianna J Klein, Kaori Tanaka, Hong Wen, Tatiana G Kutateladze, Xiaobing ShiAbstract:The euchromatin histone methyltransferase 2 (also known as G9a) methylates histone H3K9 to repress gene expression, but it also acts as a coactivator for some nuclear receptors. The molecular mechanisms underlying this activation remain elusive. Here we show that G9a functions as a coactivator of the endogenous oestrogen receptor α (ERα) in breast cancer cells in a histone methylation-independent manner. G9a dimethylates ERα at K235 both in vitro and in cells. Dimethylation of ERαK235 is recognized by the Tudor Domain of PHF20, which recruits the MOF histone acetyltransferase (HAT) complex to ERα target gene promoters to deposit histone H4K16 acetylation promoting active transcription. Together, our data suggest the molecular mechanism by which G9a functions as an ERα coactivator. Along with the PHF20/MOF complex, G9a links the crosstalk between ERα methylation and histone acetylation that governs the epigenetic regulation of hormonal gene expression.
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readers of histone methylarginine marks
Biochimica et Biophysica Acta, 2014Co-Authors: Sitaram Gayatri, Mark T BedfordAbstract:Abstract 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.
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loss of the methyl lysine effector protein phf20 impacts the expression of genes regulated by the lysine acetyltransferase mof
Journal of Biological Chemistry, 2012Co-Authors: Aimee I Badeaux, Yanzhong Yang, Kim Cardenas, Vidyasiri Vemulapalli, Kaifu Chen, Donna F Kusewitt, Ellen R Richie, Mark T BedfordAbstract:In epigenetic signaling pathways, histone tails are heavily modified, resulting in the recruitment of effector molecules that can influence transcription. One such molecule, plant homeoDomain finger protein 20 (PHF20), uses a Tudor Domain to read dimethyl lysine residues and is a known component of the MOF (male absent on the first) histone acetyltransferase protein complex, suggesting it plays a role in the cross-talk between lysine methylation and histone acetylation. We sought to investigate the biological role of PHF20 by generating a knockout mouse. Without PHF20, mice die shortly after birth and display a wide variety of phenotypes within the skeletal and hematopoietic systems. Mechanistically, PHF20 is not required for maintaining the global H4K16 acetylation levels or locus specific histone acetylation but instead works downstream in transcriptional regulation of MOF target genes.
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TDRD3 is an Effector Molecule for Arginine Methylated Histone Marks
Molecular cell, 2010Co-Authors: Yanzhong Yang, Alexsandra Espejo, Shoudan Liang, Mark T BedfordAbstract:Specific sites of histone tail methylation are associated with transcriptional activity at gene loci. These methyl marks are interpreted by effector molecules, which harbor protein Domains that bind the methylated motifs and facilitate either active or inactive states of transcription. CARM1 and PRMT1 are transcriptional coactivators that deposit H3R17me2a and H4R3me2a marks, respectively. We used a protein Domain microarray approach to identify the Tudor Domain-containing protein TDRD3 as a "reader" of these marks. Importantly, TDRD3 itself is a transcriptional coactivator. This coactivator activity requires an intact Tudor Domain. TDRD3 is recruited to an estrogen-responsive element in a CARM1-dependent manner. Furthermore, ChIP-seq analysis of TDRD3 reveals that it is predominantly localized to transcriptional start sites. Thus, TDRD3 is an effector molecule that promotes transcription by binding methylarginine marks on histone tails.
Mamoru Sato - One of the best experts on this subject based on the ideXlab platform.
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structure of the uhrf1 tandem Tudor Domain bound to a methylated non histone protein lig1 reveals rules for binding and regulation
Structure, 2019Co-Authors: Satomi Kori, Laure Ferry, Shohei Matano, Tomohiro Jimenji, Noriyuki Kodera, Takeshi Tsusaka, Rumie Matsumura, Takashi Oda, Mamoru SatoAbstract:Summary The protein UHRF1 is crucial for DNA methylation maintenance. The tandem Tudor Domain (TTD) of UHRF1 binds histone H3K9me2/3 with micromolar affinity, as well as unmethylated linker regions within UHRF1 itself, causing auto-inhibition. Recently, we showed that a methylated histone-like region of DNA ligase 1 (LIG1K126me2/me3) binds the UHRF1 TTD with nanomolar affinity, permitting UHRF1 recruitment to chromatin. Here we report the crystal structure of the UHRF1 TTD bound to a LIG1K126me3 peptide. The data explain the basis for the high TTD-binding affinity of LIG1K126me3 and reveal that the interaction may be regulated by phosphorylation. Binding of LIG1K126me3 switches the overall structure of UHRF1 from a closed to a flexible conformation, suggesting that auto-inhibition is relieved. Our results provide structural insight into how UHRF1 performs its key function in epigenetic maintenance.
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recognition of modification status on a histone h3 tail by linked histone reader modules of the epigenetic regulator uhrf1
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Kyohei Arita, Takashi Oda, Shin Isogai, Motoko Unoki, Kazuya Sugita, Naotaka Sekiyama, Keiko Kuwata, Ryuji Hamamoto, Hidehito Tochio, Mamoru SatoAbstract:Multiple covalent modifications on a histone tail are often recognized by linked histone reader modules. UHRF1 [ubiquitin-like, containing plant homeoDomain (PHD) and really interesting new gene (RING) finger Domains 1], an essential factor for maintenance of DNA methylation, contains linked two-histone reader modules, a tandem Tudor Domain and a PHD finger, tethered by a 17-aa linker, and has been implicated to link histone modifications and DNA methylation. Here, we present the crystal structure of the linked histone reader modules of UHRF1 in complex with the amino-terminal tail of histone H3. Our structural and biochemical data provide the basis for combinatorial readout of unmodified Arg-2 (H3-R2) and methylated Lys-9 (H3-K9) by the tandem Tudor Domain and the PHD finger. The structure reveals that the intermodule linker plays an essential role in the formation of a histone H3–binding hole between the reader modules by making extended contacts with the tandem Tudor Domain. The histone H3 tail fits into the hole by adopting a compact fold harboring a central helix, which allows both of the reader modules to simultaneously recognize the modification states at H3-R2 and H3-K9. Our data also suggest that phosphorylation of a linker residue can modulate the relative position of the reader modules, thereby altering the histone H3–binding mode. This finding implies that the linker region plays a role as a functional switch of UHRF1 involved in multiple regulatory pathways such as maintenance of DNA methylation and transcriptional repression.
Song Tan - One of the best experts on this subject based on the ideXlab platform.
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Piccolo NuA4-Catalyzed Acetylation of Nucleosomal Histones: Critical Roles of an Esa1 Tudor/Chromo Barrel Loop and an Epl1 Enhancer of Polycomb A
2016Co-Authors: Epca Basic Region, Jiehuan Huang, Song TanAbstract:Piccolo NuA4 is an essential yeast histone acetyltransferase (HAT) complex that targets histones H4 and H2A in nucleosome substrates. While Piccolo NuA4’s catalytic subunit Esa1 alone is unable to acetylate nucleosomal histones, its accessory subunits, Yng2 and Epl1, enable Esa1 to bind to and to act on nucleosomes. We previously determined that the Tudor Domain of Esa1 and the EPcA homology Domain of Epl1 play critical roles in Piccolo NuA4’s ability to act on the nucleosome. In this work, we pin-point a loop within the Esa1 Tudor Domain and a short basic region at the N terminus of the Epl1 EPcA Domain as necessary for this nucleosomal HAT activity. We also show that this Esa1 Tudor Domain loop region is positioned close to nucleosomal DNA and that the Epl1 EPcA basic region is in proximity to the N-terminal histone H2A tail, the globular region of histone H4, and also to nucleosomal DNA when Piccolo NuA4 interacts with the nucleosome. Since neither region identified is required for Pic-colo NuA4 to bind to nucleosomes and yet both are needed to acetylate nucleosomes, these regions may function after the en-zyme binds nucleosomes to disengage substrate histone tails from nucleosomal DNA. The regulation of gene expression in eukaryotic cells involves acomplex orchestration of chromatin enzymes that modify or remodel the chromatin assembly of histone proteins and DNA (1, 2). Much has been learned about the identity and activities of chromatinmodification and remodeling enzymes, andwe are also beginning to appreciate the different genetic pathways throug
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piccolo nua4 catalyzed acetylation of nucleosomal histones critical roles of an esa1 Tudor chromo barrel loop and an epl1 enhancer of polycomb a epca basic region
Molecular and Cellular Biology, 2013Co-Authors: Jiehuan Huang, Song TanAbstract:Piccolo NuA4 is an essential yeast histone acetyltransferase (HAT) complex that targets histones H4 and H2A in nucleosome substrates. While Piccolo NuA4's catalytic subunit Esa1 alone is unable to acetylate nucleosomal histones, its accessory subunits, Yng2 and Epl1, enable Esa1 to bind to and to act on nucleosomes. We previously determined that the Tudor Domain of Esa1 and the EPcA homology Domain of Epl1 play critical roles in Piccolo NuA4's ability to act on the nucleosome. In this work, we pinpoint a loop within the Esa1 Tudor Domain and a short basic region at the N terminus of the Epl1 EPcA Domain as necessary for this nucleosomal HAT activity. We also show that this Esa1 Tudor Domain loop region is positioned close to nucleosomal DNA and that the Epl1 EPcA basic region is in proximity to the N-terminal histone H2A tail, the globular region of histone H4, and also to nucleosomal DNA when Piccolo NuA4 interacts with the nucleosome. Since neither region identified is required for Piccolo NuA4 to bind to nucleosomes and yet both are needed to acetylate nucleosomes, these regions may function after the enzyme binds nucleosomes to disengage substrate histone tails from nucleosomal DNA.
Utz Fischer - One of the best experts on this subject based on the ideXlab platform.
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structural basis for dimethylarginine recognition by the Tudor Domains of human smn and spf30 proteins
Nature Structural & Molecular Biology, 2011Co-Authors: Konstantinos Tripsianes, Utz Fischer, Tobias Madl, Martin Machyna, Dimitrios Fessas, Clemens Englbrecht, Karla M Neugebauer, Michael SattlerAbstract:Dimethylated arginine (DMA) marks are recognized by Tudor Domain–containing proteins and play a role in the assembly of ribonucleoprotein complexes. Structural analysis of prototypic Tudor Domains from SMN and SPF30 in complex with DMA reveals the recognition mode of DMA, enabling the design of an optimized binding pocket.
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direct interaction of the spinal muscular atrophy disease protein smn with the small nucleolar rna associated protein fibrillarin
Journal of Biological Chemistry, 2001Co-Authors: Kevin W Jones, Utz Fischer, Karen Gorzynski, Chadwick M Hales, Farah Badbanchi, Rebecca M Terns, Michael P TernsAbstract:Disruption of the survival motor neuron (SMN) gene leads to selective loss of spinal motor neurons, resulting in the fatal human neurodegenerative disorder spinal muscular atrophy (SMA). SMN has been shown to function in spliceosomal small nuclear ribonucleoprotein (snRNP) biogenesis and pre-mRNA splicing. We have demonstrated that SMN also interacts with fibrillarin, a highly conserved nucleolar protein that is associated with all Box C/D small nucleolar RNAs and functions in processing and modification of rRNA. Fibrillarin and SMN co-immunoprecipitate from HeLa cell extracts indicating that the proteins exist as a complex in vivo. Furthermore, in vitro binding studies indicate that the interaction between SMN and fibrillarin is direct and salt-stable. We show that the glycine/arginine-rich Domain of fibrillarin is necessary and sufficient for SMN binding and that the region of SMN encoded by exon 3, including the Tudor Domain, mediates the binding of fibrillarin. Tudor Domain missense mutations, including one found in an SMA patient, impair the interaction between SMN and fibrillarin (as well as the common snRNP protein SmB). Our results suggest a function for SMN in small nucleolar RNP biogenesis (akin to its known role as an snRNP assembly factor) and reveal a potential link between small nucleolar RNP biogenesis and SMA.
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smn Tudor Domain structure and its interaction with the sm proteins
Nature Structural & Molecular Biology, 2001Co-Authors: Philipp Selenko, Remco Sprangers, Gunter Stier, Dirk Buhler, Utz Fischer, Michael SattlerAbstract:Spinal muscular atrophy (SMA) is a common motor neuron disease that results from mutations in the Survival of Motor Neuron (SMN) gene. The SMN protein plays a crucial role in the assembly of spliceosomal uridine-rich small nuclear ribonucleoprotein (U snRNP) complexes via binding to the spliceosomal Sm core proteins. SMN contains a central Tudor Domain that facilitates the SMN-Sm protein interaction. A SMA-causing point mutation (E134K) within the SMN Tudor Domain prevents Sm binding. Here, we have determined the three-dimensional structure of the Tudor Domain of human SMN. The structure exhibits a conserved negatively charged surface that is shown to interact with the C-terminal Arg and Gly-rich tails of Sm proteins. The E134K mutation does not disrupt the Tudor structure but affects the charge distribution within this binding site. An intriguing structural similarity between the Tudor Domain and the Sm proteins suggests the presence of an additional binding interface that resembles that in hetero-oligomeric complexes of Sm proteins. Our data provide a structural basis for a molecular defect underlying SMA.
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essential role for the Tudor Domain of smn in spliceosomal u snrnp assembly implications for spinal muscular atrophy
Human Molecular Genetics, 1999Co-Authors: Dirk Buhler, Veronica A Raker, Reinhard Luhrmann, Utz FischerAbstract:Spinal muscular atrophy (SMA) is a neurodegenerative disease of spinal motor neurons caused by reduced levels of functional survival of motor neurons (SMN) protein. SMN is part of a macromolecular complex that contains the SMN-interacting protein 1 (SIP1) and spliceosomal Sm proteins. Although it is clear that SIP1 as a component of this complex is essential for spliceosomal uridine-rich small ribonucleoprotein (U snRNP) assembly, the role of SMN and its functional interactions with SIP1 and Sm proteins are poorly understood. Here we show that the central region of SMN comprising a Tudor Domain facilitates direct binding to Sm proteins. Strikingly, the SMA-causing missense mutation E134K within the Tudor Domain severely reduced the ability of SMN to interact with Sm proteins. Moreover, antibodies directed against the Tudor Domain prevent Sm protein binding to SMN and abolish assembly of U snRNPs in vivo. Thus, our data show that SMN is an essential U snRNP assembly factor and establish a direct correlation between defects in the biogenesis of U snRNPs and SMA.
Ramesh S. Pillai - One of the best experts on this subject based on the ideXlab platform.
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exonuclease Domain containing 1 enhances miwi2 pirna biogenesis via its interaction with tdrd12
Cell Reports, 2018Co-Authors: Radha Raman Pandey, Ravi Sachidanandam, David Homolka, Opeyemi Olotu, Noora Kotaja, Ramesh S. PillaiAbstract:Summary PIWI proteins and their associated small RNAs, called PIWI-interacting RNAs (piRNAs), restrict transposon activity in animal gonads to ensure fertility. Distinct biogenesis pathways load piRNAs into the PIWI proteins MILI and MIWI2 in the mouse male embryonic germline. While most MILI piRNAs are derived via a slicer-independent pathway, MILI slicing loads MIWI2 with a series of phased piRNAs. Tudor Domain-containing 12 (TDRD12) and its interaction partner Exonuclease Domain-containing 1 (EXD1) are required for loading MIWI2, but only Tdrd12 is essential for fertility, leaving us with no explanation for the physiological role of Exd1. Using an artificial piRNA precursor, we demonstrate that MILI-triggered piRNA biogenesis is greatly reduced in the Exd1 mutant. The situation deteriorates in the sensitized Exd1 mutant (Exd1−/−;Tdrd12+/−), where diminished MIWI2 piRNA levels de-repress LINE1 retrotransposons, leading to infertility. Thus, EXD1 enhances MIWI2 piRNA biogenesis via a functional interaction with TDRD12.
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loss of the mili interacting Tudor Domain containing protein 1 activates transposons and alters the mili associated small rna profile
Nature Structural & Molecular Biology, 2009Co-Authors: Takashi Tanaka, Thomas Franz, Alexander Stark, Ramesh S. PillaiAbstract:piRNAs have been implicated in transposon silencing. Tudor Domain–containing protein-1 (Tdrd1) is now shown to interact with the mouse Piwi ortholog Mili and be part of a complex that contains Mili-associated piRNAs. Interaction occurs through the N terminus of Mili, which is dimethylated, a modification that promotes Tdrd1 interaction. The Tdrd1 mutant shares phenotypes with the Mili mutant but shows a strong effect on the nature of the small RNA pool associated with Mili.
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loss of the mili interacting Tudor Domain containing protein 1 activates transposons and alters the mili associated small rna profile
Nature Structural & Molecular Biology, 2009Co-Authors: Michael Reuter, Shinichiro Chuma, Takashi Tanaka, Thomas Franz, Alexander Stark, Ramesh S. PillaiAbstract:Piwi proteins and their associated Piwi-interacting RNAs (piRNAs) are implicated in transposon silencing in the mouse germ line. There is currently little information on additional proteins in the murine Piwi complex and how they might regulate the entry of transcripts that accumulate as piRNAs in the Piwi ribonucleoprotein (piRNP). We isolated Mili-containing complexes from adult mouse testes and identified Tudor Domain-containing protein-1 (Tdrd1) as a factor specifically associated with the Mili piRNP throughout spermatogenesis. Complex formation is promoted by the recognition of symmetrically dimethylated arginines at the N terminus of Mili by the Tudor Domains of Tdrd1. Similar to a Mili mutant, mice lacking Tdrd1 show derepression of L1 transposons accompanied by a loss of DNA methylation at their regulatory elements and delocalization of Miwi2 from the nucleus to the cytoplasm. Finally, we show that Mili piRNPs devoid of Tdrd1 accept the entry of abundant cellular transcripts into the piRNA pathway and accumulate piRNAs with a profile that is drastically different from that of the wild type. Our data suggest that Tdrd1 ensures the entry of correct transcripts into the normal piRNA pool.
