scholarly journals Structure, Activity and Function of the NSD3 Protein Lysine Methyltransferase

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 726
Author(s):  
Philipp Rathert
Keyword(s):  
Current Knowledge ◽  
Histone H3 ◽  
Set Domain ◽  
Histone Methyltransferases ◽  
Structure Activity ◽  
Lysine Methyltransferase ◽  
Active Transcription ◽  
Biochemical Mechanisms ◽  
And Function ◽  
Tumor Types

NSD3 is one of six H3K36-specific lysine methyltransferases in metazoans, and the methylation of H3K36 is associated with active transcription. NSD3 is a member of the nuclear receptor-binding SET domain (NSD) family of histone methyltransferases together with NSD1 and NSD2, which generate mono- and dimethylated lysine on histone H3. NSD3 is mutated and hyperactive in some human cancers, but the biochemical mechanisms underlying such dysregulation are barely understood. In this review, the current knowledge of NSD3 is systematically reviewed. Finally, the molecular and functional characteristics of NSD3 in different tumor types according to the current research are summarized.

scholarly journals Siglec Signaling in the Tumor Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Eline J. H. van Houtum ◽  
Christian Büll ◽  
Lenneke A. M. Cornelissen ◽  
Gosse J. Adema
Keyword(s):  
Sialic Acid ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Current Knowledge ◽  
Surface Distribution ◽  
Tumor Immune Evasion ◽  
Binding Preference ◽  
Ligand Expression ◽  
And Function ◽  
Tumor Types

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of receptors that recognize sialoglycans – sialic acid containing glycans that are abundantly present on cell membranes. Siglecs are expressed on most immune cells and can modulate their activity and function. The majority of Siglecs contains immune inhibitory motifs comparable to the immune checkpoint receptor PD-1. In the tumor microenvironment (TME), signaling through the Siglec-sialoglycan axis appears to be enhanced through multiple mechanisms favoring tumor immune evasion similar to the PD-1/PD-L1 signaling pathway. Siglec expression on tumor-infiltrating immune cells appears increased in the immune suppressive microenvironment. At the same time, enhanced Siglec ligand expression has been reported for several tumor types as a result of aberrant glycosylation, glycan modifications, and the increased expression of sialoglycans on proteins and lipids. Siglec signaling has been identified as important regulator of anti-tumor immunity in the TME, but the key factors contributing to Siglec activation by tumor-associated sialoglycans are diverse and poorly defined. Among others, Siglec activation and signaling are co-determined by their expression levels, cell surface distribution, and their binding preferences for cis- and trans-ligands in the TME. Siglec binding preference are co-determined by the nature of the proteins/lipids to which the sialoglycans are attached and the multivalency of the interaction. Here, we review the current understanding and emerging conditions and factors involved in Siglec signaling in the TME and identify current knowledge gaps that exist in the field.

scholarly journals The Structure, Activity, and Function of the SETD3 Protein Histidine Methyltransferase

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1040
Author(s):  
Apolonia Witecka ◽  
Sebastian Kwiatkowski ◽  
Takao Ishikawa ◽  
Jakub Drozak
Keyword(s):  
Protein S ◽  
Biological Processes ◽  
Set Domain ◽  
Hypoxic Conditions ◽  
Structure Activity ◽  
Mammalian Tissues ◽  
Bona Fide ◽  
And Function ◽  
Actin Protein ◽  
Cytoskeleton Integrity

SETD3 has been recently identified as a long sought, actin specific histidine methyltransferase that catalyzes the Nτ-methylation reaction of histidine 73 (H73) residue in human actin or its equivalent in other metazoans. Its homologs are widespread among multicellular eukaryotes and expressed in most mammalian tissues. SETD3 consists of a catalytic SET domain responsible for transferring the methyl group from S-adenosyl-L-methionine (AdoMet) to a protein substrate and a RuBisCO LSMT domain that recognizes and binds the methyl-accepting protein(s). The enzyme was initially identified as a methyltransferase that catalyzes the modification of histone H3 at K4 and K36 residues, but later studies revealed that the only bona fide substrate of SETD3 is H73, in the actin protein. The methylation of actin at H73 contributes to maintaining cytoskeleton integrity, which remains the only well characterized biological effect of SETD3. However, the discovery of numerous novel methyltransferase interactors suggests that SETD3 may regulate various biological processes, including cell cycle and apoptosis, carcinogenesis, response to hypoxic conditions, and enterovirus pathogenesis. This review summarizes the current advances in research on the SETD3 protein, its biological importance, and role in various diseases.

scholarly journals Arabidopsis S2Lb links AtCOMPASS-like and SDG2 activity in histone H3 Lys-4 trimethylation independently from histone H2B monoubiquitination

2019 ◽  
Author(s):  
Anne-Sophie Fiorucci ◽  
Clara Bourbousse ◽  
Lorenzo Concia ◽  
Martin Rougée ◽  
Anne-Flore Deton-Cabanillas ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Arabidopsis Thaliana ◽  
Histone H3 ◽  
Set Domain ◽  
Histone H2b ◽  
High Molecular Weight Complex ◽  
Genomic Distribution ◽  
Histone Methyltransferases ◽  
Evolutionarily Conserved ◽  
Large Repertoire

AbstractThe functional determinants of histone H3 Lys-4 trimethylation (H3K4me3), their potential dependency on histone H2B monoubiquitination (H2Bub) and their contribution to defining transcriptional regimes are poorly defined in plant systems. Unlike inS. cerevisiae, where a single SET1 protein catalyzes H3 Lys-4 trimethylation as part of COMPASS (COMPlex of proteins ASsociated with Set1), inArabidopsis thalianathis activity involves multiple histone methyltransferases (HMTs). Among these, the plant-specific SDG2 (SET DOMAIN GROUP2) has a prominent role. We report that SDG2 co-regulates hundreds of genes with SWD2-like b (S2Lb), a plant ortholog of the Swd2 axillary subunit of yeast COMPASS. S2Lb co-purifies with the AtCOMPASS core subunit WDR5 from a high-molecular weight complex, and both S2Lb and SDG2 directly influence H3K4me3 enrichment over highly transcribed genes.S2Lbknockout triggers pleiotropic developmental phenotypes at the vegetative and reproductive stages, including reduced fertility and seed dormancy. Notwithstanding,s2lbseedlings display little transcriptomic defects as compared to the large repertoire of genes targeted by S2Lb, SDG2 or H3 Lys-4 trimethylation, suggesting that H3K4me3 enrichment is important for optimal gene induction during cellular transitions rather than for determining on/off transcriptional status. Moreover, unlike in budding yeast, most of the S2Lb and H3K4me3 genomic distribution does not rely on a trans-histone crosstalk with histone H2B monoubiquitination. Collectively, this study unveils that the evolutionarily conserved COMPASS-like complex has been coopted by the plant-specific SDG2 HMT and mediates H3K4me3 deposition through an H2Bub-independent pathway in Arabidopsis.

scholarly journals Structure, Activity, and Function of the Protein Lysine Methyltransferase G9a

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1082
Author(s):  
Coralie Poulard ◽  
Lara M. Noureddine ◽  
Ludivine Pruvost ◽  
Muriel Le Romancer
Keyword(s):  
Transcriptional Repression ◽  
Cancer Biology ◽  
Structural Features ◽  
Cellular Mechanisms ◽  
Post Translational Modifications ◽  
Structure Activity ◽  
Lysine Residues ◽  
Lysine Methyltransferase ◽  
And Function ◽  
Insight Into

G9a is a lysine methyltransferase catalyzing the majority of histone H3 mono- and dimethylation at Lys-9 (H3K9), responsible for transcriptional repression events in euchromatin. G9a has been shown to methylate various lysine residues of non-histone proteins and acts as a coactivator for several transcription factors. This review will provide an overview of the structural features of G9a and its paralog called G9a-like protein (GLP), explore the biochemical features of G9a, and describe its post-translational modifications and the specific inhibitors available to target its catalytic activity. Aside from its role on histone substrates, the review will highlight some non-histone targets of G9a, in order gain insight into their role in specific cellular mechanisms. Indeed, G9a was largely described to be involved in embryonic development, hypoxia, and DNA repair. Finally, the involvement of G9a in cancer biology will be presented.

scholarly journals The N Terminus of Drosophila ESC Binds Directly to Histone H3 and Is Required for E(Z)-Dependent Trimethylation of H3 Lysine 27

2007 ◽  
Vol 27 (6) ◽  
pp. 2014-2026 ◽  
Author(s):  
Feng Tie ◽  
Carl A. Stratton ◽  
Rebeccah L. Kurzhals ◽  
Peter J. Harte
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Histone H3 ◽  
Polycomb Group ◽  
Set Domain ◽  
Chromatin Immunoprecipitation Assay ◽  
Polycomb Repressive Complex 2 ◽  
Polycomb Response Element ◽  
Evolutionarily Conserved ◽  
Hmtase Activity ◽  
And Function

ABSTRACT Polycomb group proteins mediate heritable transcriptional silencing and function through multiprotein complexes that methylate and ubiquitinate histones. The 600-kDa E(Z)/ESC complex, also known as Polycomb repressive complex 2 (PRC2), specifically methylates histone H3 lysine 27 (H3 K27) through the intrinsic histone methyltransferase (HMTase) activity of the E(Z) SET domain. By itself, E(Z) exhibits no detectable HMTase activity and requires ESC for methylation of H3 K27. The molecular basis for this requirement is unknown. ESC binds directly, via its C-terminal WD repeats (β-propeller domain), to E(Z). Here, we show that the N-terminal region of ESC that precedes its β-propeller domain interacts directly with histone H3, thereby physically linking E(Z) to its substrate. We show that when expressed in stable S2 cell lines, an N-terminally truncated ESC (FLAG-ESC61-425), like full-length ESC, is incorporated into complexes with E(Z) and binds to a Ubx Polycomb response element in a chromatin immunoprecipitation assay. However, incorporation of this N-terminally truncated ESC into E(Z) complexes prevents trimethylation of histone H3 by E(Z). We also show that a closely related Drosophila melanogaster paralog of ESC, ESC-like (ESCL), and the mammalian homolog of ESC, EED, also interact with histone H3 via their N termini, indicating that the interaction of ESC with histone H3 is evolutionarily conserved, reflecting its functional importance. Our data suggest that one of the roles of ESC (and ESCL and EED) in PRC2 complexes is to enable E(Z) to utilize histone H3 as a substrate by physically linking enzyme and substrate.

scholarly journals Structure of the Neurospora SET Domain Protein DIM-5, a Histone H3 Lysine Methyltransferase

Cell ◽  
2002 ◽  
Vol 111 (1) ◽  
pp. 117-127 ◽  
Author(s):  
Xing Zhang ◽  
Hisashi Tamaru ◽  
Seema I. Khan ◽  
John R. Horton ◽  
Lisa J. Keefe ◽  
...  
Keyword(s):  
Histone H3 ◽  
Set Domain ◽  
Lysine Methyltransferase ◽  
Domain Protein

scholarly journals Multiple Myeloma-Related WHSC1/MMSET Isoform RE-IIBP Is a Histone Methyltransferase with Transcriptional Repression Activity

2008 ◽  
Vol 28 (6) ◽  
pp. 2023-2034 ◽  
Author(s):  
Ji-Young Kim ◽  
Hae Jin Kee ◽  
Nak-Won Choe ◽  
Sung-Mi Kim ◽  
Gwang-Hyeon Eom ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Transcriptional Repression ◽  
Histone H3 ◽  
Histone Methyltransferase ◽  
Set Domain ◽  
Interleukin 5 ◽  
Hmtase Activity ◽  
Critical Residues ◽  
Tumor Types

ABSTRACT Histone methylation is crucial for transcriptional regulation and chromatin remodeling. It has been suggested that the SET domain containing protein RE-IIBP (interleukin-5 [IL-5] response element II binding protein) may perform a function in the carcinogenesis of certain tumor types, including myeloma. However, the pathogenic role of RE-IIBP in these diseases remains to be clearly elucidated. In this study, we have conducted an investigation into the relationship between the histone-methylating activity of RE-IIBP and transcriptional regulation. Here, we report that RE-IIBP is up-regulated in the blood cells of leukemia patients, and we characterized the histone H3 lysine 27 (H3-K27) methyltransferase activity of RE-IIBP. Point mutant analysis revealed that SET domain cysteine 483 and arginine 477 are critical residues for the histone methyltransferase (HMTase) activity of RE-IIBP. RE-IIBP also represses basal transcription via histone deacetylase (HDAC) recruitment, which may be mediated by H3-K27 methylation. In the chromatin immunoprecipitation assays, we showed that RE-IIBP overexpression induces histone H3-K27 methylation, HDAC recruitment, and histone H3 hypoacetylation on the IL-5 promoter and represses expression. Conversely, short hairpin RNA-mediated knockdown of RE-IIBP reduces histone H3-K27 methylation and HDAC occupancy around the IL-5 promoter. These data illustrate the important regulatory role of RE-IIBP in transcriptional regulation, thereby pointing to the important role of HMTase activity in carcinogenesis.

scholarly journals SETDB1-Mediated Silencing of Retroelements

Viruses ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 596 ◽  
Author(s):  
Kei Fukuda ◽  
Yoichi Shinkai
Keyword(s):  
Genome Stability ◽  
Histone H3 ◽  
Endogenous Retroviruses ◽  
H3k9 Methylation ◽  
Epigenetic Factors ◽  
Set Domain ◽  
H3k9 Trimethylation ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase

SETDB1 (SET domain bifurcated histone lysine methyltransferase 1) is a protein lysine methyltransferase and methylates histone H3 at lysine 9 (H3K9). Among other H3K9 methyltransferases, SETDB1 and SETDB1-mediated H3K9 trimethylation (H3K9me3) play pivotal roles for silencing of endogenous and exogenous retroelements, thus contributing to genome stability against retroelement transposition. Furthermore, SETDB1 is highly upregulated in various tumor cells. In this article, we describe recent advances about how SETDB1 activity is regulated, how SETDB1 represses various types of retroelements such as L1 and class I, II, and III endogenous retroviruses (ERVs) in concert with other epigenetic factors such as KAP1 and the HUSH complex and how SETDB1-mediated H3K9 methylation can be maintained during replication.

Effects of Maternal Obesity and Gestational Diabetes Mellitus on the Placenta: Current Knowledge and Targets for Therapeutic Interventions

2020 ◽  
Vol 19 (2) ◽  
pp. 176-192
Author(s):  
Samantha Bedell ◽  
Janine Hutson ◽  
Barbra de Vrijer ◽  
Genevieve Eastabrook
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Maternal Obesity ◽  
Environmental Changes ◽  
Current Knowledge ◽  
Therapeutic Interventions ◽  
Placental Development ◽  
Exchange Site ◽  
And Function

: Obesity and gestational diabetes mellitus (GDM) are becoming more common among pregnant women worldwide and are individually associated with a number of placenta-mediated obstetric complications, including preeclampsia, macrosomia, intrauterine growth restriction and stillbirth. The placenta serves several functions throughout pregnancy and is the main exchange site for the transfer of nutrients and gas from mother to fetus. In pregnancies complicated by maternal obesity or GDM, the placenta is exposed to environmental changes, such as increased inflammation and oxidative stress, dyslipidemia, and altered hormone levels. These changes can affect placental development and function and lead to abnormal fetal growth and development as well as metabolic and cardiovascular abnormalities in the offspring. This review aims to summarize current knowledge on the effects of obesity and GDM on placental development and function. Understanding these processes is key in developing therapeutic interventions with the goal of mitigating these effects and preventing future cardiovascular and metabolic pathology in subsequent generations.

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