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https://www.readbyqxmd.com/read/28934823/comprehensive-analysis-of-non-synonymous-natural-variants-of-g-protein-coupled-receptors
#1
Hee Ryung Kim, Nguyen Minh Duc, Ka Young Chung
G protein-coupled receptors (GPCRs) are the largest superfamily of transmembrane receptors and have vital signaling functions in various organs. Because of their critical roles in physiology and pathology, GPCRs are the most commonly used therapeutic target. It has been suggested that GPCRs undergo massive genetic variations such as genetic polymorphisms and DNA insertions or deletions. Among these genetic variations, non-synonymous natural variations change the amino acid sequence and could thus alter GPCR functions such as expression, localization, signaling, and ligand binding, which may be involved in disease development and altered responses to GPCR-targeting drugs...
September 19, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28934671/the-hnf1a-mutant-ala180val-clinical-challenges-in-determining-causality-of-a-rare-hnf1a-variant-in-familial-diabetes
#2
J V Sagen, L Bjørkhaug, B I Haukanes, L Grevle, J Molnes, B G Nedrebø, O Søvik, P R Njølstad, S Johansson, A Molven
AIMS: Heterozygous mutations in hepatocyte nuclear factor-1A (HNF1A) cause maturity-onset diabetes of the young type 3 (MODY3). Our aim was to compare two families with suspected dominantly inherited diabetes and a new HNF1A variant of unknown clinical significance. METHODS: The HNF1A gene was sequenced in two independently recruited families from the Norwegian MODY Registry. Both familes were phenotyped clinically and biochemically. Microsatellite markers around and within the HNF1A locus were used for haplotyping...
September 1, 2017: Diabetes Research and Clinical Practice
https://www.readbyqxmd.com/read/28934500/a-synthetic-dna-binding-inhibitor-of-sox2-guides-human-induced-pluripotent-stem-cells-to-differentiate-into-mesoderm
#3
Junichi Taniguchi, Ganesh N Pandian, Takuya Hidaka, Kaori Hashiya, Toshikazu Bando, Kyeong Kyu Kim, Hiroshi Sugiyama
Targeted differentiation of human induced pluripotent stem cells (hiPSCs) using only chemicals would have value-added clinical potential in the regeneration of complex cell types including cardiomyocytes. Despite the availability of several chemical inhibitors targeting proteins involved in signaling pathways, no bioactive synthetic DNA-binding inhibitors, targeting key cell fate-controlling genes such as SOX2, are yet available. Here, we demonstrate a novel DNA-based chemical approach to guide the differentiation of hiPSCs using pyrrole-imidazole polyamides (PIPs), which are sequence-selective DNA-binding synthetic molecules...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934494/derivatives-of-bst-like-gss-polymerase-with-improved-processivity-and-inhibitor-tolerance
#4
Igor P Oscorbin, Ekaterina A Belousova, Ulyana A Boyarskikh, Aleksandr I Zakabunin, Evgeny A Khrapov, Maksim L Filipenko
At the moment, one of the actual trends in medical diagnostics is a development of methods for practical applications such as point-of-care testing, POCT or research tools, for example, whole genome amplification, WGA. All the techniques are based on using of specific DNA polymerases having strand displacement activity, high synthetic processivity, fidelity and, most significantly, tolerance to contaminants, appearing from analysed biological samples or collected under purification procedures. Here, we have designed a set of fusion enzymes based on catalytic domain of DNA polymerase I from Geobacillus sp...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934483/the-fused-snoal_2-domain-in-the-mycobacterium-tuberculosis-sigma-factor-%C3%AF-j-modulates-promoter-recognition
#5
Kapil Goutam, Arvind K Gupta, Balasubramanian Gopal
Extra-cytoplasmic function (ECF) σ-factors are widespread in bacteria, linking environmental stimuli with changes in gene expression. These transcription factors span several phylogenetically distinct groups and are remarkably diverse in their activation and regulatory mechanisms. Here, we describe the structural and biochemical features of a Mycobacterium tuberculosis ECF factor σJ that suggests that the SnoaL_2 domain at the C-terminus can modulate the activity of this initiation factor in the absence of a cognate regulatory anti-σ factor...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934472/controlled-re-activation-of-epigenetically-silenced-tet-promoter-driven-transgene-expression-by-targeted-demethylation
#6
Natascha Gödecke, Lisha Zha, Shawal Spencer, Sara Behme, Pamela Riemer, Michael Rehli, Hansjörg Hauser, Dagmar Wirth
Faithful expression of transgenes in cell cultures and mice is often challenged by locus dependent epigenetic silencing. We investigated silencing of Tet-controlled expression cassettes within the mouse ROSA26 locus. We observed pronounced DNA methylation of the Tet promoter concomitant with loss of expression in mES cells as well as in differentiated cells and transgenic animals. Strikingly, the ROSA26 promoter remains active and methylation free indicating that this silencing mechanism specifically affects the transgene, but does not spread to the host's chromosomal neighborhood...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934470/monitoring-replication-protein-a-rpa-dynamics-in-homologous-recombination-through-site-specific-incorporation-of-non-canonical-amino-acids
#7
Nilisha Pokhrel, Sofia Origanti, Eric Parker Davenport, Disha Gandhi, Kyle Kaniecki, Ryan A Mehl, Eric C Greene, Chris Dockendorff, Edwin Antony
An essential coordinator of all DNA metabolic processes is Replication Protein A (RPA). RPA orchestrates these processes by binding to single-stranded DNA (ssDNA) and interacting with several other DNA binding proteins. Determining the real-time kinetics of single players such as RPA in the presence of multiple DNA processors to better understand the associated mechanistic events is technically challenging. To overcome this hurdle, we utilized non-canonical amino acids and bio-orthogonal chemistry to site-specifically incorporate a chemical fluorophore onto a single subunit of heterotrimeric RPA...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934209/microbial-translocation-is-correlated-with-hiv-evolution-in-hiv-hcv-co-infected-patients
#8
Jean-Jacques Tudesq, Catherine Dunyach-Remy, Christophe Combescure, Régine Doncesco, Didier Laureillard, Jean-Philippe Lavigne, Albert Sotto
Microbial translocation (MT) is characterized by bacterial products passing into the blood through the gut barrier and is a key phenomenon in the pathophysiology of Human Immunodeficiency Virus (HIV) infection. MT is also associated with liver damage in Hepatitis C Virus (HCV) patients. The aim of the study was to assess MT in plasma of HIV-HCV co-infected patients. 16S rDNA (16 S Ribosomal DNA subunit) marker and other markers of MT such as Lipopolysaccharide (LPS)-binding protein (LBP), soluble CD14 (sCD14), intestinal fatty acid binding protein (I-FABP) were used...
2017: PloS One
https://www.readbyqxmd.com/read/28933851/design-and-structure-guided-development-of-novel-inhibitors-of-the-xeroderma-pigmentosum-group-a-xpa-protein-dna-interaction
#9
Navnath S Gavande, Pamela VanderVere-Carozza, Akaash K Mishra, Tyler L Vernon, Katherine S Pawelczak, John J Turchi
XPA is a unique and essential protein required for the nucleotide excision DNA repair pathway and represents a therapeutic target in oncology. Herein, we are the first to develop novel inhibitors of the XPA-DNA interaction through structure-guided drug design efforts. Ester derivatives of the compounds 1 (X80), 22, and 24 displayed excellent inhibitory activity (IC50 of 0.82 ± 0.18 μM and 1.3 ± 0.22 μM, respectively) but poor solubility. We have synthesized novel amide derivatives that retain potency and have much improved solubility...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28933684/screening-of-primary-gp120-immunogens-to-formulate-the-next-generation-polyvalent-dna-prime-protein-boost-hiv-1-vaccines
#10
Shixia Wang, Te-Hui Wu, Anthony Hackett, Veronica Efros, Yan Wang, Dong Han, Aaron Wallace, Yuxin Chen, Guangnan Hu, Shuying Liu, Paul Clapham, James Arthos, David Montefiori, Shan Lu
Our previous preclinical studies and a Phase I clinical trial DP6-001 have indicated that a polyvalent Env formulation was able to elicit broadly reactive antibody responses including low titer neutralizing antibody responses against viral isolates of subtypes A, B, C and AE. In the current report, a panel of 62 gp120 immunogens were screened in a rabbit model to identify gp120 immunogens that can elicit improved binding and neutralizing antibody responses and some of them can be included in the next polyvalent formulation...
September 21, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28932319/dna-hypomethylation-of-a-transcription-factor-binding-site-within-the-promoter-of-a-gout-risk-gene-nrbp1-upregulates-its-expression-by-inhibition-of-tfap2a-binding
#11
Zaihua Zhu, Weida Meng, Peiru Liu, Xiaoxia Zhu, Yun Liu, Hejian Zou
BACKGROUND: Genome-wide association studies (GWASs) have identified dozens of loci associated with gout, but for most cases, the risk genes and the underlying molecular mechanisms contributing to these associations are unknown. This study sought to understand the molecular mechanism of a common genetic variant, rs780093, in the development of gout, both in vitro and in vivo. RESULTS: Nuclear receptor binding protein 1 (NRBP1), as a gout risk gene, and its regulatory region, 72 bp upstream of the transcription start site, designated as B1, were identified through integrative analyses of genome-wide genotype and DNA methylation data...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28932107/bioinformatics-study-of-m-9053g-a-mutation-at-the-atp6-gene-in-relation-to-type-2-diabetes-mellitus-and-cataract-diseases
#12
Iman Permana Maksum, Sandy Risfi Saputra, Nenden Indrayati, Muhammad Yusuf, Toto Subroto
The mitochondrial disease often associated with various illnesses in relation to the activity of cells metabolites and the synthesis of adenosine triphosphate (ATP), including alteration in the mitochondrial DNA. The mutation of m.9053G>A at the ATP6 gene was found in patients with type 2 diabetes mellitus (DM type 2) and cataract. Therefore, this mutation is predicted to be clinical features of the 2 diseases. ATP6 gene encodes protein subunit of ATPase6, a part of ATP synthase, which is important in the electron transfer and proton translocation in intracellular respiration system...
2017: Bioinformatics and Biology Insights
https://www.readbyqxmd.com/read/28931919/ror%C3%AE-2-requires-lsd1-to-enhance-tumor-progression-in-breast-cancer
#13
Kyeongkyu Kim, Ji Min Lee, Young Suk Yu, Hyunkyung Kim, Hye Jin Nam, Hyeong-Gon Moon, Dong-Young Noh, Keun Il Kim, Sungsoon Fang, Sung Hee Baek
Retinoic acid-related orphan receptor α (RORα) regulates diverse physiological processes, including inflammatory responses, lipid metabolism, circadian rhythm, and cancer biology. RORα has four different isoforms which have distinct N-terminal domains but share identical DNA binding domain and ligand binding domain in human. However, lack of specific antibody against each RORα isoform makes biochemical studies on each RORα isoform remain unclear. Here, we generate RORα2-specific antibody and characterize the role of RORα2 in promoting tumor progression in breast cancer...
September 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28931603/the-pyhin-protein-p205-regulates-the-inflammasome-by-controlling-asc-expression
#14
Sreya Ghosh, Christina Wallerath, Sergio Covarrubias, Veit Hornung, Susan Carpenter, Katherine A Fitzgerald
Members of the IFN-inducible PYHIN protein family, such as absent in melanoma-2 and IFN-γ-inducible protein (IFI)16, bind dsDNA and form caspase-1-activating inflammasomes that are important in immunity to cytosolic bacteria, DNA viruses, or HIV. IFI16 has also been shown to regulate transcription of type I IFNs during HSV infection. The role of other members of the PYHIN protein family in the regulation of immune responses is much less clear. In this study, we identified an immune-regulatory function for a member of the murine PYHIN protein family, p205 (also called Ifi205)...
September 20, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28931413/topological-organization-and-dynamic-regulation-of-human-trna-genes-during-macrophage-differentiation
#15
Kevin Van Bortle, Douglas H Phanstiel, Michael P Snyder
BACKGROUND: The human genome is hierarchically organized into local and long-range structures that help shape cell-type-specific transcription patterns. Transfer RNA (tRNA) genes (tDNAs), which are transcribed by RNA polymerase III (RNAPIII) and encode RNA molecules responsible for translation, are dispersed throughout the genome and, in many cases, linearly organized into genomic clusters with other tDNAs. Whether the location and three-dimensional organization of tDNAs contribute to the activity of these genes has remained difficult to address, due in part to unique challenges related to tRNA sequencing...
September 20, 2017: Genome Biology
https://www.readbyqxmd.com/read/28930687/the-rab2b-garil5-complex-promotes-cytosolic-dna-induced-innate-immune-responses
#16
Michihiro Takahama, Mitsunori Fukuda, Norihiko Ohbayashi, Tatsuya Kozaki, Takuma Misawa, Toru Okamoto, Yoshiharu Matsuura, Shizuo Akira, Tatsuya Saitoh
Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that induces the IFN antiviral response. However, the regulatory mechanisms that mediate cGAS-triggered signaling have not been fully explored. Here, we show the involvement of a small GTPase, RAB2B, and its effector protein, Golgi-associated RAB2B interactor-like 5 (GARIL5), in the cGAS-mediated IFN response. RAB2B-deficiency affects the IFN response induced by cytosolic DNA. Consistent with this, RAB2B deficiency enhances replication of vaccinia virus, a DNA virus...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28930672/histone-h3-methylated-at-arginine-17-is-essential-for-reprogramming-the-paternal-genome-in-zygotes
#17
Yuki Hatanaka, Takeshi Tsusaka, Natsumi Shimizu, Kohtaro Morita, Takehiro Suzuki, Shinichi Machida, Manabu Satoh, Arata Honda, Michiko Hirose, Satoshi Kamimura, Narumi Ogonuki, Toshinobu Nakamura, Kimiko Inoue, Yoshihiko Hosoi, Naoshi Dohmae, Toru Nakano, Hitoshi Kurumizaka, Kazuya Matsumoto, Yoichi Shinkai, Atsuo Ogura
At fertilization, the paternal genome undergoes extensive reprogramming through protamine-histone exchange and active DNA demethylation, but only a few maternal factors have been defined in these processes. We identified maternal Mettl23 as a protein arginine methyltransferase (PRMT), which most likely catalyzes the asymmetric dimethylation of histone H3R17 (H3R17me2a), as indicated by in vitro assays and treatment with TBBD, an H3R17 PRMT inhibitor. Maternal histone H3.3, which is essential for paternal nucleosomal assembly, is unable to be incorporated into the male pronucleus when it lacks R17me2a...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28930533/53bp1-a-guardian-for-centrosomal-integrity
#18
Haeyoung Kim, Hyungshin Yim
53BP1 is known as a mediator in DNA damage response and a regulator of DNA double-stranded breaks (DSBs) repair. 53BP1 was recently reported to be a centrosomal protein and a binding partner of mitotic polo-like kinase 1 (Plk1). The stability of 53BP1, in response to DSBs, is regulated by its phosphorylation, deubiquitination, and ubiquitination. During mitosis, 53BP1 is stabilized by phosphorylation at S380, a putative binding region with polo-box domain of Plk1, and deubiquitination by ubiquitin-specific protease 7 (USP7)...
January 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28930109/abcg2-regulatory-single-nucleotide-polymorphisms-alter-in-vivo-enhancer-activity-and-expression
#19
Rachel J Eclov, Mee J Kim, Aparna Chhibber, Robin P Smith, Nadav Ahituv, Deanna L Kroetz
OBJECTIVES: The expression and activity of the breast cancer resistance protein (ABCG2) contributes toward the pharmacokinetics of endogenous and xenobiotic substrates. The effect of genetic variation on the activity of cis-regulatory elements and nuclear response elements in the ABCG2 locus and their contribution toward ABCG2 expression have not been investigated systematically. In this study, the effect of genetic variation on the in-vitro and in-vivo enhancer activity of six previously identified liver enhancers in the ABCG2 locus was examined...
September 18, 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28928952/a-simple-method-to-measure-clock-bmal1-dna-binding-activity-in-tissue-and-cell-extracts
#20
Maud Gillessen, Pieter Bas Kwak, Alfred Tamayo
The proteins CLOCK and BMAL1 form a heterodimeric transcription factor essential to circadian rhythms in mammals.  Daily rhythms of CLOCK-BMAL1 DNA binding activity are known to oscillate with target gene expression in vivo. Here we present a highly sensitive assay that recapitulates native CLOCK-BMAL1 DNA binding rhythms from crude tissue extracts, which we call the Clock Protein-DNA Binding Assay (CPDBA). This method can detect less than 2-fold differences in DNA binding activity, and can deliver results in two hours or less using 10 microliters or less of crude extract, while requiring neither specialized equipment nor expensive probes...
2017: F1000Research
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