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Barry M Zee, Amy B Dibona, Artyom A Alekseyenko, Christopher A French, Mitzi I Kuroda
Defects in chromatin proteins frequently manifest in diseases. A striking case of a chromatin-centric disease is NUT-midline carcinoma (NMC), which is characterized by expression of NUT as a fusion partner most frequently with BRD4. ChIP-sequencing studies from NMC patients revealed that BRD4-NUT (B4N) covers large genomic regions and elevates transcription within these domains. To investigate how B4N modulates chromatin, we performed affinity purification of B4N when ectopically expressed in 293-TREx cells and quantified the associated histone posttranslational modifications (PTM) using proteomics...
2016: PloS One
Catherine G Heath, Nicolas Viphakone, Stuart A Wilson
TRanscription and EXport (TREX) is a conserved multisubunit complex essential for embryogenesis, organogenesis and cellular differentiation throughout life. By linking transcription, mRNA processing and export together, it exerts a physiologically vital role in the gene expression pathway. In addition, this complex prevents DNA damage and regulates the cell cycle by ensuring optimal gene expression. As the extent of TREX activity in viral infections, amyotrophic lateral sclerosis and cancer emerges, the need for a greater understanding of TREX function becomes evident...
October 1, 2016: Biochemical Journal
Yu Yang, Honggui La, Kai Tang, Daisuke Miki, Lan Yang, Bangshing Wang, Cheng-Guo Duan, Wenfeng Nie, Xingang Wang, Siwen Wang, Yufeng Pan, Elizabeth J Tran, Lizhe An, Huiming Zhang, Jian-Kang Zhu
Epigenetic regulation is important for organismal development and response to the environment. Alteration in epigenetic status has been known mostly from the perspective of enzymatic actions of DNA methylation and/or histone modifications. In a genetic screen for cellular factors involved in preventing epigenetic silencing, we isolated an Arabidopsis mutant defective in SAC3B, a component of the conserved TREX-2 complex that couples mRNA transcription with nuleo-cytoplasmic export. Arabidopsis SAC3B dysfunction causes gene silencing at transgenic and endogenous loci, accompanied by elevation in the repressive histone mark H3K9me2 and by reduction in RNA polymerase Pol II occupancy...
September 26, 2016: Nucleic Acids Research
Nwet Nwet Win, Takuya Ito, Yi Yi Win, Hla Ngwe, Takeshi Kodama, Ikuro Abe, Hiroyuki Morita
Viral protein R (Vpr) is an accessory protein that plays important roles in the viral pathogenesis of Human Immunodeficiency Virus-1 (HIV-1). An assay for anti-Vpr activity, using TREx-HeLa-Vpr cells, is a promising strategy to discover Vpr inhibitors. The anti-Vpr assay revealed that the CHCl3-soluble extract of Picrasma javanica bark possesses potent anti-Vpr activity. Furthermore, studies of quassinoids (1-15) previously isolated from the extract demonstrated that all of the tested quassinoids exhibit anti-Vpr activity...
October 1, 2016: Bioorganic & Medicinal Chemistry Letters
Mariana Serpeloni, Elena Jiménez-Ruiz, Newton Medeiros Vidal, Constanze Kroeber, Nicole Andenmatten, Leandro Lemgruber, Patricia Mörking, Gurman S Pall, Markus Meissner, Andréa R Ávila
Nucleo-cytoplasmic RNA export is an essential post-transcriptional step to control gene expression in eukaryotic cells and is poorly understood in apicomplexan parasites. With the exception of UAP56, a component of TREX (Transcription Export) complex, other components of mRNA export machinery are not well conserved in divergent supergroups. Here we use Toxoplasma gondii as a model system to functionally characterize TgUAP56 and its potential interaction factors. We demonstrate that TgUAP56 is crucial for mRNA export and that functional interference leads to significant accumulation of mRNA in the nucleus...
August 20, 2016: Molecular Microbiology
David A Jacques, William A McEwan, Laura Hilditch, Amanda J Price, Greg J Towers, Leo C James
During the early stages of infection, the HIV-1 capsid protects viral components from cytosolic sensors and nucleases such as cGAS and TREX, respectively, while allowing access to nucleotides for efficient reverse transcription. Here we show that each capsid hexamer has a size-selective pore bound by a ring of six arginine residues and a 'molecular iris' formed by the amino-terminal β-hairpin. The arginine ring creates a strongly positively charged channel that recruits the four nucleotides with on-rates that approach diffusion limits...
August 18, 2016: Nature
Arunava Roy, Dipanjan Dutta, Jawed Iqbal, Gina Pisano, Olsi Gjyshi, Mairaj Ahmed Ansari, Binod Kumar, Bala Chandran
UNLABELLED: IFI16 (interferon gamma-inducible protein 16) recognizes nuclear episomal herpesvirus (Kaposi's sarcoma-associated herpesvirus [KSHV], Epstein-Barr virus [EBV], and herpes simplex virus 1 [HSV-1]) genomes and induces the inflammasome and interferon beta responses. It also acts as a lytic replication restriction factor and inhibits viral DNA replication (human cytomegalovirus [HCMV] and human papillomavirus [HPV]) and transcription (HSV-1, HCMV, and HPV) through epigenetic modifications of the viral genomes...
October 1, 2016: Journal of Virology
Shintaro Aibara, Xiao-Chen Bai, Murray Stewart
UNLABELLED: Transcription-export complex 2 (TREX-2 complex) facilitates the localization of actively transcribing genes to the nuclear periphery and also functions to contribute to the generation of export-competent mRNPs through interactions with the general mRNA nuclear export factor Mex67:Mtr2. The TREX-2 complex is based on a Sac3 scaffold to which Thp1, Sem1, Cdc31, and Sus1 bind. TREX-2 can be subdivided into two modules: one, in which Thp1 and Sem1 bind to the Sac3(M) region (residues ∼100-551), and the other in which Cdc31 and two Sus1 chains bind to the Sac3(CID) region (residues ∼710-805)...
September 2016: Journal of Structural Biology
A N Bonchuk, P G Georgiev, O G Maksimenko
ENY2 is a multifunctional protein, a component of the SAGA complex (protein complex involved in the regulation of transcription, possessing histone-acetyltransferase and H2B-histone-deubiquitinylating activities [1]) and TREX-2 (complex involved in the mRNA nuclear export [2]). Besides this, the interactions of ENY2 with DNA-binding insulator proteins Su(Hw) and dCTCF have been described as essential for the barrier activity of corresponding insulators [3, 4]. In this study, we described the formation of mutually exclusive complexes of ENY2 with insulator proteins and Sgfl1-a component of the SAGA complex, direct binding partner for ENY2...
May 2016: Doklady. Biochemistry and Biophysics
Panapat Phairoh, Thana Suthibatpong, Triwit Rattanarojpong, Nujarin Jongruja, Saengchan Senapin, Kiattawee Choowongkomon, Pongsak Khunrae
ICP35 is a non-structural protein from White spot syndrome virus believed to be important in viral replication. Since ICP35 was found to localize in the host nucleus, it has been speculated that the function of ICP35 might be involved in the interaction of DNA. In this study, we overexpressed, purified and characterized ICP35. The thioredoxin-fused ICP35 (thio-ICP35) was strongly expressed in E. coli and be able to form itself into dimers. Investigation of the interaction between ICP35 and DNA revealed that ICP35 can perform DNase activity...
2016: PloS One
Sibo Tao, Ye Zhang, Xiaoyue Wang, Le Xu, Xiaofeng Fang, Zhi John Lu, Dong Liu
Induction and secretion of acid phosphatases (APases) is an adaptive response that plants use to cope with P (Pi) deficiency in their environment. The molecular mechanism that regulates this response, however, is poorly understood. In this work, we identified an Arabidopsis (Arabidopsis thaliana) mutant, hps8, which exhibits enhanced APase activity on its root surface (also called root-associated APase activity). Our molecular and genetic analyses indicate that this altered Pi response results from a mutation in the AtTHO1 gene that encodes a subunit of the THO/TREX protein complex...
August 2016: Plant Physiology
Junho K Hur, Yun Doo Chung
The THO/TREX complex consists of several conserved subunits and is required for mRNA export. In metazoans, THO/TREX binds a subset of mRNAs during RNA splicing, and facilitates their nuclear export. How THO/TREX selects RNA targets is, however, incompletely understood. In our recent study, we reported that THO is loaded onto Piwi-interacting RNA (piRNA) precursor transcripts independent of splicing, and facilitates convergent transcription in Drosophila ovary. The precursors are later processed into mature piRNAs, small noncoding RNAs that silence transposable elements (TEs)...
July 2016: BMB Reports
Christopher J Hale, Magdalena E Potok, Jennifer Lopez, Truman Do, Ao Liu, Javier Gallego-Bartolome, Scott D Michaels, Steven E Jacobsen
Eukaryotic genomes are regulated by epigenetic marks that act to modulate transcriptional control as well as to regulate DNA replication and repair. In Arabidopsis thaliana, mutation of the ATXR5 and ATXR6 histone methyltransferases causes reduction in histone H3 lysine 27 monomethylation, transcriptional upregulation of transposons, and a genome instability defect in which there is an accumulation of excess DNA corresponding to pericentromeric heterochromatin. We designed a forward genetic screen to identify suppressors of the atxr5/6 phenotype that uncovered loss-of-function mutations in two components of the TREX-2 complex (AtTHP1, AtSAC3B), a SUMO-interacting E3 ubiquitin ligase (AtSTUbL2) and a methyl-binding domain protein (AtMBD9)...
June 2016: PLoS Genetics
Nichole Eshleman, Guangbo Liu, Kaitlyn McGrath, Roy Parker, J Ross Buchan
The nuclear THO and TREX-2 complexes are implicated in several steps of nuclear mRNP biogenesis, including transcription, 3' end processing and export. In a recent genomic microscopy screen in Saccharomyces cerevisiae for mutants with constitutive stress granules, we identified that absence of THO and TREX-2 complex subunits leads to the accumulation of Pab1-GFP in cytoplasmic foci. We now show that these THO/TREX-2 mutant induced foci ("TT foci") are not stress granules but instead are a mRNP granule containing poly(A)(+) mRNA, some mRNP components also found in stress granules, as well several proteins involved in mRNA 3' end processing and export not normally seen in stress granules...
August 2016: RNA
Marcel Nogueira d'Eurydice, Elton Tadeu Montrazi, Carlos Alberto Fortulan, Tito José Bonagamba
This work introduces an alternative way to perform the T2 - T2 Exchange NMR experiment. Rather than varying the number of π pulses in the first CPMG cycle of the T2 - T2 Exchange NMR pulse sequence, as used to obtain the 2D correlation maps, it is fixed and small enough to act as a short T2-filter. By varying the storage time, a set of 1D measurements of T2 distributions can be obtained to reveal the effects of the migration dynamics combined with relaxation effects. This significantly reduces the required time to perform the experiment, allowing a more in-depth study of exchange dynamics and relaxation processes with improved signal-to-noise ratio...
May 28, 2016: Journal of Chemical Physics
N Sakaguchi, K Maeda
Germinal center B-cell-associated nuclear protein (GANP) is upregulated in germinal center B cells against T-cell-dependent antigens in mice and humans. In mice, GANP depletion in B cells impairs antibody affinity maturation. Conversely, its transgenic overexpression augments the generation of high-affinity antigen-specific B cells. GANP associates with AID in the cytoplasm, shepherds AID into the nucleus, and augments its access to the rearranged immunoglobulin (Ig) variable (V) region of the genome in B cells, thereby precipitating the somatic hypermutation of V region genes...
2016: Advances in Immunology
Sophie Schumann, Belinda Baquero-Perez, Adrian Whitehouse
The coupling of mRNA processing steps is essential for precise and efficient gene expression. The human transcription/export (hTREX) complex is a highly conserved multi-protein complex responsible for eukaryotic mRNA stability and nuclear export. We have previously shown that the Kaposi's sarcoma-associated open reading frame 57 (ORF57) protein orchestrates the recruitment of the hTREX complex onto viral intronless mRNA, forming a stable and export-competent viral ribonucleoprotein particle (vRNP). Recently, additional cellular proteins, namely CHTOP, CIP29 and POLDIP3 have been proposed as novel hTREX components...
August 2016: Journal of General Virology
Cesar A C Cervantes, Luanda M S Oliveira, Kelly C G Manfrere, Josenilson F Lima, Natalli Z Pereira, Alberto J S Duarte, Maria N Sato
Individuals who remain HIV-seronegative despite repeated unprotected exposure to the virus are defined as exposed seronegative (ESN) individuals. Innate and adaptive immunity, as well as genetic factors, provide ESNs with important advantages that allow for low infection susceptibility. The majority of HIV-1-infected individuals undergo antiretroviral therapy, which can decrease the level of HIV-1 exposure in ESNs. We analyzed type I interferon (IFN)-related antiviral and regulatory factors in peripheral blood mononuclear cells (PBMCs) and oral epithelial cells from serodiscordant couples...
2016: Scientific Reports
Jeffrey S Amos, Lijia Huang, Julien Thevenon, Ariana Kariminedjad, Chandree L Beaulieu, Alice Masurel-Paulet, Hossein Najmabadi, Zohreh Fattahi, Maryam Beheshtian, Seyed Hassan Tonekaboni, Sha Tang, Katherine L Helbig, Wendy Alcaraz, Jean-Baptiste Rivière, Laurence Faivre, A Micheil Innes, Robert Roger Lebel, Kym M Boycott
THOC6 is a part of the THO complex, which is involved in coordinating mRNA processing with export. The THO complex interacts with additional components to form the larger TREX complex (transcription export complex). Previously, a homozygous missense mutation in THOC6 in the Hutterite population was reported in association with syndromic intellectual disability. Using exome sequencing, we identified three unrelated patients with bi-allelic mutations in THOC6 associated with intellectual disability and additional clinical features...
April 22, 2016: Clinical Genetics
Jason A Estep, Erin L Sternburg, Gissell A Sanchez, Fedor V Karginov
BACKGROUND: Targeted genomic editing using the CRISPR/Cas9 methodology has opened exciting new avenues in probing gene function in virtually any model system, including cultured mammalian cells. Depending on the desired mutation, several experimental options exist in the isolation of clonal lines, such as selection with introduced markers, or screening by PCR amplification of genomic DNA. However, streamlined approaches to establishing deletion and tagging mutants with minimal genomic perturbation are of interest in applying this methodology...
2016: BMC Molecular Biology
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