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The Structure of the Bifunctional Everninomicin Biosynthetic Enzyme EvdMO1 Suggests Independent Activity of the Fused Methyltransferase-Oxidase Domains.
Starbird CA, Perry NA, Chen Q, Berndt S, Yamakawa I, Loukachevitch LV, Limbrick EM, Bachmann BO, Iverson TM, McCulloch KM
(2018) Biochemistry 57: 6827-6837
MeSH Terms: Amino Acid Sequence, Aminoglycosides, Bacterial Proteins, Biosynthetic Pathways, Catalytic Domain, Conserved Sequence, Crystallography, X-Ray, Gene Fusion, Genes, Bacterial, Methyltransferases, Micromonospora, Models, Molecular, Oxygenases, Protein Interaction Domains and Motifs, Sequence Homology, Amino Acid
Show Abstract · Added April 1, 2019
Members of the orthosomycin family of natural products are decorated polysaccharides with potent antibiotic activity and complex biosynthetic pathways. The defining feature of the orthosomycins is an orthoester linkage between carbohydrate moieties that is necessary for antibiotic activity and is likely formed by a family of conserved oxygenases. Everninomicins are octasaccharide orthosomycins produced by Micromonospora carbonacea that have two orthoester linkages and a methylenedioxy bridge, three features whose formation logically requires oxidative chemistry. Correspondingly, the evd gene cluster encoding everninomicin D encodes two monofunctional nonheme iron, α-ketoglutarate-dependent oxygenases and one bifunctional enzyme with an N-terminal methyltransferase domain and a C-terminal oxygenase domain. To investigate whether the activities of these domains are linked in the bifunctional enzyme EvdMO1, we determined the structure of the N-terminal methyltransferase domain to 1.1 Å and that of the full-length protein to 3.35 Å resolution. Both domains of EvdMO1 adopt the canonical folds of their respective superfamilies and are connected by a short linker. Each domain's active site is oriented such that it faces away from the other domain, and there is no evidence of a channel connecting the two. Our results support EvdMO1 working as a bifunctional enzyme with independent catalytic activities.
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15 MeSH Terms
HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis.
Choby JE, Grunenwald CM, Celis AI, Gerdes SY, DuBois JL, Skaar EP
(2018) MBio 9:
MeSH Terms: Aldehyde Oxidoreductases, Bacterial Proteins, Gene Deletion, Gene Expression, Gene Expression Regulation, Bacterial, Heme, Methyltransferases, Staphylococcus aureus
Show Abstract · Added March 15, 2018
is responsible for a significant amount of devastating disease. Its ability to colonize the host and cause infection is supported by a variety of proteins that are dependent on the cofactor heme. Heme is a porphyrin used broadly across kingdoms and is synthesized from common cellular precursors and iron. While heme is critical to bacterial physiology, it is also toxic in high concentrations, requiring that organisms encode regulatory processes to control heme homeostasis. In this work, we describe a posttranscriptional regulatory strategy in heme biosynthesis. The first committed enzyme in the heme biosynthetic pathway, glutamyl-tRNA reductase (GtrR), is regulated by heme abundance and the integral membrane protein HemX. GtrR abundance increases dramatically in response to heme deficiency, suggesting a mechanism by which responds to the need to increase heme synthesis. Additionally, HemX is required to maintain low levels of GtrR in heme-proficient cells, and inactivation of leads to increased heme synthesis. Excess heme synthesis in a Δ mutant activates the staphylococcal heme stress response, suggesting that regulation of heme synthesis is critical to reduce self-imposed heme toxicity. Analysis of diverse organisms indicates that HemX is widely conserved among heme-synthesizing bacteria, suggesting that HemX is a common factor involved in the regulation of GtrR abundance. Together, this work demonstrates that regulates heme synthesis by modulating GtrR abundance in response to heme deficiency and through the activity of the broadly conserved HemX. is a leading cause of skin and soft tissue infections, endocarditis, bacteremia, and osteomyelitis, making it a critical health care concern. Development of new antimicrobials against requires knowledge of the physiology that supports this organism's pathogenesis. One component of staphylococcal physiology that contributes to growth and virulence is heme. Heme is a widely utilized cofactor that enables diverse chemical reactions across many enzyme families. relies on many critical heme-dependent proteins and is sensitive to excess heme toxicity, suggesting must maintain proper intracellular heme homeostasis. Because provides heme for heme-dependent enzymes via synthesis from common precursors, we hypothesized that regulation of heme synthesis is one mechanism to maintain heme homeostasis. In this study, we identify that posttranscriptionally regulates heme synthesis by restraining abundance of the first heme biosynthetic enzyme, GtrR, via heme and the broadly conserved membrane protein HemX.
Copyright © 2018 Choby et al.
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8 MeSH Terms
Set2 methyltransferase facilitates cell cycle progression by maintaining transcriptional fidelity.
Dronamraju R, Jha DK, Eser U, Adams AT, Dominguez D, Choudhury R, Chiang YC, Rathmell WK, Emanuele MJ, Churchman LS, Strahl BD
(2018) Nucleic Acids Res 46: 1331-1344
MeSH Terms: Anaphase-Promoting Complex-Cyclosome, Biological Evolution, Cdc20 Proteins, Cell Cycle, Gene Expression Regulation, Fungal, Histone-Lysine N-Methyltransferase, Histones, Humans, Lysine, Methylation, Methyltransferases, Nocodazole, Protein Processing, Post-Translational, Proteolysis, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Transcription, Genetic, Tubulin Modulators
Show Abstract · Added October 30, 2019
Methylation of histone H3 lysine 36 (H3K36me) by yeast Set2 is critical for the maintenance of chromatin structure and transcriptional fidelity. However, we do not know the full range of Set2/H3K36me functions or the scope of mechanisms that regulate Set2-dependent H3K36 methylation. Here, we show that the APC/CCDC20 complex regulates Set2 protein abundance during the cell cycle. Significantly, absence of Set2-mediated H3K36me causes a loss of cell cycle control and pronounced defects in the transcriptional fidelity of cell cycle regulatory genes, a class of genes that are generally long, hence highly dependent on Set2/H3K36me for their transcriptional fidelity. Because APC/C also controls human SETD2, and SETD2 likewise regulates cell cycle progression, our data imply an evolutionarily conserved cell cycle function for Set2/SETD2 that may explain why recurrent mutations of SETD2 contribute to human disease.
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Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation.
Osipovich AB, Gangula R, Vianna PG, Magnuson MA
(2016) Development 143: 4595-4607
MeSH Terms: Acetylation, Animals, Apoptosis, Carrier Proteins, Cell Cycle, Cell Differentiation, Cell Proliferation, Cells, Cultured, Chromatin, Embryonic Development, Embryonic Stem Cells, Gene Expression Regulation, Heart Defects, Congenital, Histones, Methyltransferases, Mice, Mice, Knockout, Myocytes, Cardiac, Neural Tube, Promoter Regions, Genetic, RNA, Untranslated, Transcription, Genetic
Show Abstract · Added November 30, 2016
SET domain-containing proteins play a vital role in regulating gene expression during development through modifications in chromatin structure. Here we show that SET domain-containing 5 (Setd5) is divergently transcribed with Gt(ROSA26)Sor, is necessary for mammalian development, and interacts with the PAF1 co-transcriptional complex and other proteins. Setd5-deficient mouse embryos exhibit severe defects in neural tube formation, somitogenesis and cardiac development, have aberrant vasculogenesis in embryos, yolk sacs and placentas, and die between embryonic day 10.5 and 11.5. Setd5-deficient embryonic stem cells have impaired cellular proliferation, increased apoptosis, defective cell cycle progression, a diminished ability to differentiate into cardiomyocytes and greatly perturbed gene expression. SETD5 co-immunoprecipitates with multiple components of the PAF1 and histone deacetylase-containing NCoR complexes and is not solely required for major histone lysine methylation marks. In the absence of Setd5, histone acetylation is increased at transcription start sites and near downstream regions. These findings suggest that SETD5 functions in a manner similar to yeast Set3p and Drosophila UpSET, and that it is essential for regulating histone acetylation during gene transcription.
© 2016. Published by The Company of Biologists Ltd.
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22 MeSH Terms
Structure/Function Analysis of Recurrent Mutations in SETD2 Protein Reveals a Critical and Conserved Role for a SET Domain Residue in Maintaining Protein Stability and Histone H3 Lys-36 Trimethylation.
Hacker KE, Fahey CC, Shinsky SA, Chiang YJ, DiFiore JV, Jha DK, Vo AH, Shavit JA, Davis IJ, Strahl BD, Rathmell WK
(2016) J Biol Chem 291: 21283-21295
MeSH Terms: Enzyme Stability, Histone-Lysine N-Methyltransferase, Histones, Humans, Methylation, Methyltransferases, Mutation, Neoplasm Proteins, Neoplasms, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Structure-Activity Relationship
Show Abstract · Added October 30, 2019
The yeast Set2 histone methyltransferase is a critical enzyme that plays a number of key roles in gene transcription and DNA repair. Recently, the human homologue, SETD2, was found to be recurrently mutated in a significant percentage of renal cell carcinomas, raising the possibility that the activity of SETD2 is tumor-suppressive. Using budding yeast and human cell line model systems, we examined the functional significance of two evolutionarily conserved residues in SETD2 that are recurrently mutated in human cancers. Whereas one of these mutations (R2510H), located in the Set2 Rpb1 interaction domain, did not result in an observable defect in SETD2 enzymatic function, a second mutation in the catalytic domain of this enzyme (R1625C) resulted in a complete loss of histone H3 Lys-36 trimethylation (H3K36me3). This mutant showed unchanged thermal stability as compared with the wild type protein but diminished binding to the histone H3 tail. Surprisingly, mutation of the conserved residue in Set2 (R195C) similarly resulted in a complete loss of H3K36me3 but did not affect dimethylated histone H3 Lys-36 (H3K36me2) or functions associated with H3K36me2 in yeast. Collectively, these data imply a critical role for Arg-1625 in maintaining the protein interaction with H3 and specific H3K36me3 function of this enzyme, which is conserved from yeast to humans. They also may provide a refined biochemical explanation for how H3K36me3 loss leads to genomic instability and cancer.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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MeSH Terms
LASP-1: a nuclear hub for the UHRF1-DNMT1-G9a-Snail1 complex.
Duvall-Noelle N, Karwandyar A, Richmond A, Raman D
(2016) Oncogene 35: 1122-33
MeSH Terms: Active Transport, Cell Nucleus, Adaptor Proteins, Signal Transducing, Breast Neoplasms, CCAAT-Enhancer-Binding Proteins, Cell Line, Tumor, Chemokine CXCL12, Cytoskeletal Proteins, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases, Epigenesis, Genetic, Gene Knockdown Techniques, Heterocyclic Compounds, Histocompatibility Antigens, Histone-Lysine N-Methyltransferase, Histones, Humans, LIM Domain Proteins, Prognosis, Proteomics, Signal Transduction, Snail Family Transcription Factors, Transcription Factors, Tumor Microenvironment
Show Abstract · Added May 20, 2015
Nuclear LASP-1 (LIM and SH3 protein-1) has a direct correlation with overall survival of breast cancer patients. In this study, immunohistochemical analysis of a human breast TMA showed that LASP-1 is absent in normal human breast epithelium but the expression increases with malignancy and is highly nuclear in aggressive breast cancer. We investigated whether the chemokines and growth factors present in the tumor microenvironment could trigger nuclear translocation of LASP-1.Treatment of human breast cancer cells with CXCL12, EGF and HRG, and HMEC-CXCR2 cells with CXCL8 facilitated nuclear shuttling of LASP-1. Data from the biochemical analysis of the nuclear and cytosolic fractions further confirmed the nuclear translocation of LASP-1 upon chemokine and growth factor treatment. CXCL12-dependent nuclear import of LASP-1 could be blocked by CXCR4 antagonist, AMD-3100. Knock down of LASP-1 resulted in alterations in gene expression leading to an increased level of cell-junction and extracellular matrix proteins and an altered cytokine secretory profile. Three-dimensional cultures of human breast cancer cells on Matrigel revealed an altered colony growth, morphology and arborization pattern in LASP-1 knockdown cells. Functional analysis of the LASP-1 knockdown cells revealed increased adhesion to collagen IV and decreased invasion through the Matrigel. Proteomic analysis of immunoprecipitates of LASP-1 and subsequent validation approaches revealed that LASP-1 associated with the epigenetic machinery especially UHRF1, DNMT1, G9a and the transcription factor Snail1. Interestingly, LASP-1 associated with UHRF1, G9a, Snail1 and di- and tri-methylated histoneH3 in a CXCL12-dependent manner based on immunoprecipitation and proximity ligation assays. LASP-1 also directly bound to Snail1 which may stabilize Snail1. Thus, nuclear LASP-1 appears to functionally serve as a hub for the epigenetic machinery.
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23 MeSH Terms
Age- and pregnancy-associated DNA methylation changes in mammary epithelial cells.
Huh SJ, Clement K, Jee D, Merlini A, Choudhury S, Maruyama R, Yoo R, Chytil A, Boyle P, Ran FA, Moses HL, Barcellos-Hoff MH, Jackson-Grusby L, Meissner A, Polyak K
(2015) Stem Cell Reports 4: 297-311
MeSH Terms: Age Factors, Animals, Antigens, Surface, Cell Differentiation, Cluster Analysis, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, Enhancer Elements, Genetic, Enzyme Activation, Epigenesis, Genetic, Epithelial Cells, Female, Gene Expression Profiling, Gene Expression Regulation, Histones, Immunophenotyping, Mammary Glands, Animal, Mice, Mice, Knockout, Organ Specificity, Phenotype, Pregnancy, Promoter Regions, Genetic, Sexual Maturation, Signal Transduction
Show Abstract · Added February 5, 2016
Postnatal mammary gland development and differentiation occur during puberty and pregnancy. To explore the role of DNA methylation in these processes, we determined the genome-wide DNA methylation and gene expression profiles of CD24(+)CD61(+)CD29(hi), CD24(+)CD61(+)CD29(lo), and CD24(+)CD61(-)CD29(lo) cell populations that were previously associated with distinct biological properties at different ages and reproductive stages. We found that pregnancy had the most significant effects on CD24(+)CD61(+)CD29(hi) and CD24(+)CD61(+)CD29(lo) cells, inducing distinct epigenetic states that were maintained through life. Integrated analysis of gene expression, DNA methylation, and histone modification profiles revealed cell-type- and reproductive-stage-specific changes. We identified p27 and TGFβ signaling as key regulators of CD24(+)CD61(+)CD29(lo) cell proliferation, based on their expression patterns and results from mammary gland explant cultures. Our results suggest that relatively minor changes in DNA methylation occur during luminal differentiation compared with the effects of pregnancy on CD24(+)CD61(+)CD29(hi) and CD24(+)CD61(+)CD29(lo) cells.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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26 MeSH Terms
DNA methyltransferase 3a and mitogen-activated protein kinase signaling regulate the expression of fibroblast growth factor-inducible 14 (Fn14) during denervation-induced skeletal muscle atrophy.
Tajrishi MM, Shin J, Hetman M, Kumar A
(2014) J Biol Chem 289: 19985-99
MeSH Terms: Animals, Base Sequence, Conserved Sequence, CpG Islands, DNA, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, Gene Expression, Gene Knockdown Techniques, MAP Kinase Signaling System, Mice, Mice, Inbred C57BL, Models, Biological, Molecular Sequence Data, Muscle Denervation, Muscle, Skeletal, Muscular Atrophy, Promoter Regions, Genetic, RNA, Small Interfering, Receptors, Tumor Necrosis Factor, Sequence Homology, Nucleic Acid, Sp1 Transcription Factor, TWEAK Receptor, Transcription Factor AP-1
Show Abstract · Added October 30, 2014
The TWEAK-fibroblast growth factor-inducible 14 (Fn14) system is a critical regulator of denervation-induced skeletal muscle atrophy. Although the expression of Fn14 is a rate-limiting step in muscle atrophy on denervation, mechanisms regulating gene expression of Fn14 remain unknown. Methylation of CpG sites within promoter region is an important epigenetic mechanism for gene silencing. Our study demonstrates that Fn14 promoter contains a CpG island close to transcription start site. Fn14 promoter also contains multiple consensus DNA sequence for transcription factors activator protein 1 (AP1) and specificity protein 1 (SP1). Denervation diminishes overall genomic DNA methylation and causes hypomethylation at specific CpG sites in Fn14 promoter leading to the increased gene expression of Fn14 in skeletal muscle. Abundance of DNA methyltransferase 3a (Dnmt3a) and its interaction with Fn14 promoter are repressed in denervated skeletal muscle of mice. Overexpression of Dnmt3a inhibits the gene expression of Fn14 and attenuates skeletal muscle atrophy upon denervation. Denervation also causes the activation of ERK1/2, JNK1/2, and ERK5 MAPKs and AP1 and SP1, which stimulate the expression of Fn14 in skeletal muscle. Collectively, our study provides novel evidence that Dnmt3a and MAPK signaling regulate the levels of Fn14 in skeletal muscle on denervation.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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24 MeSH Terms
Challenges in interpreting the evidence for genetic predictors of ototoxicity.
Ratain MJ, Cox NJ, Henderson TO
(2013) Clin Pharmacol Ther 94: 631-5
MeSH Terms: Antineoplastic Agents, Catechol O-Methyltransferase, Cisplatin, Female, Genetic Variation, Hearing Loss, Humans, Male, Methyltransferases, Multidrug Resistance-Associated Proteins
Show Abstract · Added February 22, 2016
There has been recent controversy regarding predictors of cisplatin-induced ototoxicity in children, as highlighted in a previous issue of this journal. We have reviewed the two articles that purport to show an association between TPMT and COMT variants and ototoxicity, as well as the related patent applications dating back to 2006. We summarize statistical issues not fully addressed by the authors that appear to have confounded the results of their studies.
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10 MeSH Terms
NRMT2 is an N-terminal monomethylase that primes for its homologue NRMT1.
Petkowski JJ, Bonsignore LA, Tooley JG, Wilkey DW, Merchant ML, Macara IG, Schaner Tooley CE
(2013) Biochem J 456: 453-62
MeSH Terms: Catalysis, HEK293 Cells, Humans, Methylation, Methyltransferases, Substrate Specificity
Show Abstract · Added March 7, 2014
NRMT (N-terminal regulator of chromatin condensation 1 methyltransferase) was the first eukaryotic methyltransferase identified to specifically methylate the free α-amino group of proteins. Since the discovery of this N-terminal methyltransferase, many new substrates have been identified and the modification itself has been shown to regulate DNA-protein interactions. Sequence analysis predicts one close human homologue of NRMT, METTL11B (methyltransferase-like protein 11B, now renamed NRMT2). We show in the present paper for the first time that NRMT2 also has N-terminal methylation activity and recognizes the same N-terminal consensus sequences as NRMT (now NRMT1). Both enzymes have similar tissue expression and cellular localization patterns. However, enzyme assays and MS experiments indicate that they differ in their specific catalytic functions. Although NRMT1 is a distributive methyltransferase that can mono-, di- and tri-methylate its substrates, NRMT2 is primarily a monomethylase. Concurrent expression of NRMT1 and NRMT2 accelerates the production of trimethylation, and we propose that NRMT2 activates NRMT1 by priming its substrates for trimethylation.
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6 MeSH Terms