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Sebastian Scheer, Colby Zaph
G9a (KMT1C, EHMT2) is a lysine methyltransferase (KMT) whose primary function is to di-methylate lysine 9 of histone H3 (H3K9me2). G9a-dependent H3K9me2 is associated with gene silencing and acts primarily through the recruitment of H3K9me2-binding proteins that prevent transcriptional activation. Gene repression via G9a-dependent H3K9me2 is critically required in embryonic stem (ES) cells for the development of cellular lineages by repressing expression of pluripotency factors. In the immune system, lymphoid cells such as T cells and innate lymphoid cells (ILCs) can differentiate from a naïve state into one of several effector lineages that require both activating and repressive mechanisms to maintain the correct gene expression program...
2017: Frontiers in Immunology
Karine Guitot, Thierry Drujon, Fabienne Burlina, Sandrine Sagan, Sandra Beaupierre, Olivier Pamlard, Robert H Dodd, Catherine Guillou, Gérard Bolbach, Emmanuelle Sachon, Dominique Guianvarc'h
Histone lysine methylation is associated with essential biological functions like transcription activation or repression, depending on the position and the degree of methylation. This post-translational modification is introduced by protein lysine methyltransferases (KMTs) which catalyze the transfer of one to three methyl groups from the methyl donor S-adenosyl-L-methionine (AdoMet) to the amino group on the side chain of lysines. The regulation of protein lysine methylation plays a primary role not only in the basic functioning of normal cells but also in various pathologies and KMT deregulation is associated with diseases including cancer...
April 7, 2017: Analytical and Bioanalytical Chemistry
Vinay Kumar Aileni, Erna Davydova, Anders Moen, Pål Ø Falnes
A number of lysine-specific methyltransferases (KMTs) are responsible for the post-translational modification of cellular proteins on lysine residues. Most KMTs typically recognize specific motifs in unstructured, short peptide sequences. However, we have recently discovered a novel KMT that appeared to have a more relaxed sequence specificity, namely, valosin-containing protein (VCP)-KMT, which trimethylates Lys-315 in the molecular chaperone VCP. On the basis of this, here, we explored the possibility of using the VCP-KMT/VCP system to obtain specific lysine methylation of desired sequences grafted onto a VCP-derived scaffold...
February 28, 2017: ACS Omega
Sebastian F Winter, Franziska Loebel, Jorg Dietrich
BACKGROUND: Coined as the "Warburg effect" and a recognized hallmark of cancer, energy metabolism is aberrantly geared towards aerobic glycolysis in most human cancers, including malignant glioma. Ketogenic metabolic therapy (KMT), i.e. nutritional intervention with ketogenic or low-glycemic diets, has been proposed as an anti-neoplastic strategy in glioma patients. MATERIALS AND METHODS: We here review the rationale and existing data investigating KMT in management of patients with malignant glioma and discuss the promise and potential challenges of this novel strategy...
April 2017: Critical Reviews in Oncology/hematology
Adi Zipin-Roitman, Nasma Aqaqe, Muhammad Yassin, Shahar Biechonski, Mariam Amar, Mark F van Delft, Olga I Gan, Sean P McDermott, Alla Buzina, Troy Ketela, Liran Shlush, Stephanie Xie, Veronique Voisin, Jason Moffat, Mark D Minden, John E Dick, Michael Milyavsky
The molecular determinants governing escape of Acute Myeloid Leukemia (AML) cells from DNA damaging therapy remain poorly defined and account for therapy failures. To isolate genes responsible for leukemia cells regeneration following multiple challenges with irradiation we performed a genome-wide shRNA screen. Some of the isolated hits are known players in the DNA damage response (e.g. p53, CHK2), whereas other, e.g. SMYD2 lysine methyltransferase (KMT), remains uncharacterized in the AML context. Here we report that SMYD2 knockdown confers relative resistance to human AML cells against multiple classes of DNA damaging agents...
March 7, 2017: Oncotarget
Vladan Vučković, Dragana Vujović
A chemistry module with the aqueous chemistry coupled with the complex 3D nonhydrostatic atmospheric model is used to investigate how the representation of gas-aqueous mass transfer and ice retention affect the SO2 redistribution in the presence of a convective cloud. Gas uptake to the liquid water is calculated using both Henry's law equilibrium (HE) and kinetic mass transport (KMT). The constant retention coefficients for SO2 (k ret = 0.46) and for H2O2 (k ret = 0.64) are used. It is shown that the amount of SO2 in the air at higher altitudes (10-12 km) is greater when partial retention (PR) is included...
February 2017: Environmental Science and Pollution Research International
Yoichi Munehira, Ze Yang, Or Gozani
Histone methylation dynamics plays a critical role in cellular programming during development. For example, specific lysine methyltransferases (KMTs) and lysine demethylases (KDMs) have been implicated in the differentiation of mesenchymal stem cells into various cell lineages. However, a systematic and functional analysis for an entire family of KMT or KDM enzymes has not been performed. Here, we test the function of all the known and candidate KDMs in myoblast and osteoblast differentiation using the C2C12 cell differentiation model system...
October 11, 2016: Journal of Molecular Biology
Ciro Milite, Alessandra Feoli, Monica Viviano, Donatella Rescigno, Agostino Cianciulli, Amodio Luca Balzano, Antonello Mai, Sabrina Castellano, Gianluca Sbardella
SETD8/SET8/Pr-SET7/KMT5A is the only known lysine methyltransferase (KMT) that monomethylates lysine 20 of histone H4 (H4K20) in vivo. Lysine residues of non-histone proteins including proliferating cell nuclear antigen (PCNA) and p53 are also monomethylated. As a consequence, the methyltransferase activity of the enzyme is implicated in many essential cellular processes including DNA replication, DNA damage response, transcription modulation, and cell cycle regulation. This review aims to provide an overview of the roles of SETD8 in physiological and pathological pathways and to discuss the progress made to date in inhibiting the activity of SETD8 by small molecules, with an emphasis on their discovery, selectivity over other methyltransferases and cellular activity...
2016: Clinical Epigenetics
Annic Baumgartner, Noemi Zueger, Annika Bargetzi, Michael Medinger, Jakob R Passweg, Zeno Stanga, Beat Mueller, Mario Bargetzi, Philipp Schuetz
INTRODUCTION: In acute myeloid leukemia (AML) patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT), there is uncertainty about the extent of influence nutritional parameters have on clinical outcomes. In this study, we investigated the association between initial body mass index (BMI) and weight loss during HSCT on clinical outcomes in a well-characterised cohort of AML patients. METHODS: We analysed data of the Basel stem-cell transplantation registry ('KMT Kohorte') including all patients with AML undergoing first allogeneic HSCT from January 2003 to January 2014...
2016: Annals of Nutrition & Metabolism
Christèle Maison, Delphine Bailly, Jean-Pierre Quivy, Geneviève Almouzni
The trimethylation of histone H3 on lysine 9 (H3K9me3) - a mark recognized by HP1 that depends on the Suv39h lysine methyltransferases (KMTs) - has provided a basis for the reader/writer model to explain HP1 accumulation at pericentric heterochromatin in mammals. Here, we identify the Suv39h1 paralog, as a unique enhancer of HP1α sumoylation both in vitro and in vivo. The region responsible for promoting HP1α sumoylation (aa1-167) is distinct from the KMT catalytic domain and mediates binding to Ubc9. Tethering the 1-167 domain of Suv39h1 to pericentric heterochromatin, but not mutants unable to bind Ubc9, accelerates the de novo targeting of HP1α to these domains...
2016: Nature Communications
Pål Ø Falnes, Magnus E Jakobsson, Erna Davydova, Angela Ho, Jędrzej Małecki
Methylation of biomolecules is a frequent biochemical reaction within the cell, and a plethora of highly specific methyltransferases (MTases) catalyse the transfer of a methyl group from S-adenosylmethionine (AdoMet) to various substrates. The posttranslational methylation of lysine residues, catalysed by numerous lysine (K)-specific protein MTases (KMTs), is a very common and important protein modification, which recently has been subject to intense studies, particularly in the case of histone proteins. The majority of KMTs belong to a class of MTases that share a defining 'SET domain', and these enzymes mostly target lysines in the flexible tails of histones...
July 15, 2016: Biochemical Journal
Lin Fu, Hailong Wu, Steven Y Cheng, Daming Gao, Lei Zhang, Yun Zhao
Hedgehog signaling plays very important roles in development and cancers. Vertebrates have three transcriptional factors, Gli1, Gli2 and Gli3. Among them, Gli3 is a very special transcriptional factor which closely resembles Cubitus interruptus (Ci, in Drosophila) structurally and functionally as a 'double agent' for Shh target gene expression. Here we show that Gli3 full-length, but not the truncated form, can be methylated at K436 and K595. This methylation is specifically catalyzed by Set7, a lysine methyltransferase (KMT)...
2016: ELife
Z Gibb, C G Grupen, W M C Maxwell, L H A Morris
REASONS FOR PERFORMING STUDY: The fertility of sex-sorted, cryopreserved stallion sperm must be improved for the sex-sorting technology to be applied commercially. OBJECTIVES: To optimise the conditions used to liquid store stallion sperm prior to sex-sorting and assess the fertility of sperm following sex-sorting and cryopreservation. STUDY DESIGN: Both in vitro experiment and randomised controlled trial in healthy, client-owned mares. METHODS: Stallion ejaculates (n = 9) were diluted in either a skimmed milk (KMT) or BSA (I-BSA) based media to 25 × 10(6) sperm/ml directly (+SP25) or washed to remove seminal plasma and diluted to 25 or 111 × 10(6) sperm/ml (-SP25 and -SP111)...
March 2017: Equine Veterinary Journal
Jędrzej Małecki, Helge-André Dahl, Anders Moen, Erna Davydova, Pål Ø Falnes
Human METTL20 is a mitochondrial, lysine-specific methyltransferase that methylates the β-subunit of electron transfer flavoprotein (ETFβ). Interestingly, putative METTL20 orthologues are found in a subset of α-proteobacteria, including Agrobacterium tumefaciens Using an activity-based approach, we identified in bacterial extracts two substrates of recombinant METTL20 from A. tumefaciens (AtMETTL20), namely ETFβ and the ribosomal protein RpL7/L12. We show that AtMETTL20, analogous to the human enzyme, methylates ETFβ on Lys-193 and Lys-196 both in vitro and in vivo ETF plays a key role in mediating electron transfer from various dehydrogenases, and we found that its electron transferring ability was diminished by AtMETTL20-mediated methylation of ETFβ...
April 29, 2016: Journal of Biological Chemistry
Carolin C Lechner, Ninad D Agashe, Beat Fierz
Nucleosomes carry extensive post-translational modifications (PTMs), which results in complex modification patterns that are involved in epigenetic signaling. Although two copies of each histone coexist in a nucleosome, they may not carry the same PTMs and are often differently modified (asymmetric). In bivalent domains, a chromatin signature prevalent in embryonic stem cells (ESCs), namely H3 methylated at lysine 4 (H3K4me3), coexists with H3K27me3 in asymmetric nucleosomes. We report a general, modular, and traceless method for producing asymmetrically modified nucleosomes...
February 18, 2016: Angewandte Chemie
Michal Halperin-Sternfeld, Hadar Zigdon-Giladi, Eli E Machtei
AIM: The aim of this study was to retrospectively evaluate the association between shallow vestibular depth (VD) and peri-implant parameters. MATERIAL AND METHODS: Peri-implant parameters were evaluated in 61 periodontal patients under regular supportive periodontal therapy. Clinical parameters included gingival index (GI), plaque index (PI), bleeding on probing (BOP), peri-implant pocket depths (PPD), mucosal recession (MR), relative attachment level (RAL), width and thickness of keratinized mucosa (KMW, KMT) and VD...
March 2016: Journal of Clinical Periodontology
Danilo Maeda Reino, Luciana Prado Maia, Patrícia Garani Fernandes, Sergio Luis Scombatti de Souza, Mario Taba Junior, Daniela Bazan Palioto, Marcio Fermandes de Moraes Grisi, Arthur Belém Novaes
The aim of this randomized controlled clinical study was to compare the extended flap technique (EFT) with the coronally advanced flap technique (CAF) using a porcine collagen matrix (PCM) for root coverage. Twenty patients with two bilateral gingival recessions, Miller class I or II on non-molar teeth were treated with CAF+PCM (control group) or EFT+PCM (test group). Clinical measurements of probing pocket depth (PPD), clinical attachment level (CAL), recession height (RH), keratinized tissue height (KTH), keratinized mucosa thickness (KMT) were determined at baseline, 3 and 6 months post-surgery...
October 2015: Brazilian Dental Journal
Jae-Young Lee, Se-Hwan Lee, Sun-Hee Heo, Kwang-Soo Kim, Changhoon Kim, Dae-Kwan Kim, Jeong-Jae Ko, Kyung-Soon Park
G9a is a lysine methyltransferase (KMTase) for histone H3 lysine 9 that plays critical roles in a number of biological processes. Emerging evidence suggests that aberrant expression of G9a contributes to tumor metastasis and maintenance of a malignant phenotype in cancer by inducing epigenetic silencing of tumor suppressor genes. Here, we show that G9a regulates Sox2 protein stability in breast cancer cells. When G9a lysine methyltransferase activity was chemically inhibited in the ER(+) breast cancer cell line MCF7, Sox2 protein levels were decreased...
2015: PloS One
Lijuan Zhu, Zhikai Wang, Wenwen Wang, Chunli Wang, Shasha Hua, Zeqi Su, Larry Brako, Minerva Garcia-Barrio, Mingliang Ye, Xuan Wei, Hanfa Zou, Xia Ding, Lifang Liu, Xing Liu, Xuebiao Yao
Mitotic chromosome segregation is orchestrated by the dynamic interaction of spindle microtubules with the kinetochores. During chromosome alignment, kinetochore-bound microtubules undergo dynamic cycles between growth and shrinkage, leading to an oscillatory movement of chromosomes along the spindle axis. Although kinetochore protein CENP-H serves as a molecular control of kinetochore-microtubule dynamics, the mechanistic link between CENP-H and kinetochore microtubules (kMT) has remained less characterized...
November 6, 2015: Journal of Biological Chemistry
Larissa Lezina, Vasilisa Aksenova, Olga Fedorova, Daria Malikova, Oleg Shuvalov, Alexey V Antonov, Dmitri Tentler, Alexander V Garabadgiu, Gerry Melino, Nikolai A Barlev
Genotoxic stress inflicted by anti-cancer drugs causes DNA breaks and genome instability. DNA double strand breaks induced by irradiation or pharmacological inhibition of Topoisomerase II activate ATM (ataxia-telangiectasia-mutated) kinase signalling pathway that in turn triggers cell cycle arrest and DNA repair. ATM-dependent gamma-phosphorylation of histone H2Ax and other histone modifications, including ubiquitnylation, promote exchange of histones and recruitment of DNA damage response (DDR) and repair proteins...
September 22, 2015: Oncotarget
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