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Spliceosome

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https://www.readbyqxmd.com/read/29448241/comprehensive-analysis-of-differentially-expressed-profiles-of-alzheimer-s-disease-associated-circular-rnas-in-an-alzheimer-s-disease-mouse-model
#1
Jin-Lan Huang, Mei-Chun Qin, Yan Zhou, Zhe-Hao Xu, Si-Man Yang, Fan Zhang, Jing Zhong, Ming-Kun Liang, Ben Chen, Wen-Yan Zhang, Deng-Pan Wu, Zhen-Guo Zhong
Circular RNAs (circRNAs), a novel kind of non-coding RNA, have received increasing attention for their involvement in pathogenesis of Alzheimer's disease (AD); however, few studies have reported in the characterization and function of AD associated circRNAs. Here the expression profiles of circRNAs in 5- and 10-month-old SAMP8 mice were identified using circRNA microarray and found that 85 dysregulated circRNAs were observed in 10-month-old SAMP8 versus control mice and 231 circRNAs exhibited differential expression in 10-month-old SAMP8 versus 5-month-old SAMP8...
February 15, 2018: Aging
https://www.readbyqxmd.com/read/29437235/exome-sequencing-reveals-three-homozygous-missense-variants-in-snrpa-in-two-sisters-with-syndromic-intellectual-disability
#2
M M Rangel-Sosa, L E Figuera-Villanueva, I A González-Ramos, Y X Pérez-Páramo, L A Martínez-Jacobo, L Arnaud-López, J A Nastasi-Catanese, A M Rivas-Estilla, K A Galán-Huerta, A Rojas-Martínez, R Ortiz-López, C Córdova-Fletes
Splicing-related gene mutations might affect the expression of a single gene or multiple genes and cause clinically heterogeneous diseases. With the advent of next-generation sequencing, several splicing gene mutations have been exposed, yet most major spliceosome genes have no reports of germline mutations and therefore, their effects are largely unknown. We describe the previously unreported concurrence of intellectual disability, short stature, poor speech, and minor craniofacial and hand anomalies in two female siblings with three homozygous missense variants in SNRPA (a component of the U1 small nuclear ribonucleoprotein complex) characterized by homozygosity mapping and whole exome sequencing...
February 13, 2018: Clinical Genetics
https://www.readbyqxmd.com/read/29435927/gene-silencing-in-vitro-and-in-vivo-using-intronic-micrornas
#3
Shi-Lung Lin, Shao-Yao Ying
MicroRNAs (miRNAs), small single-stranded regulatory RNAs capable of interfering with intracellular messenger RNAs (mRNAs) that contain either complete or partial complementarity, are useful for the design of new therapies against cancer polymorphism and viral mutation. Numerous miRNAs have been reported to induce RNA interference (RNAi), a post-transcriptional gene-silencing mechanism. Recent evidence also indicates that they are involved in the transcriptional regulation of genome activities. They were first discovered in Caenorhabditis elegans as native RNA fragments that modulate a wide range of genetic regulatory pathways during embryonic development, and are now recognized as small gene silencers transcribed from the noncoding regions of a genome...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29419415/spliceosomal-components-protect-embryonic-neurons-from-r-loop-mediated-dna-damage-and-apoptosis
#4
Shelly Sorrells, Sara Nik, Mattie Casey, Rosannah C Cameron, Harold Truong, Cristhian Toruno, Michelle Gulfo, Albert Lowe, Cicely Jette, Rodney A Stewart, Teresa V Bowman
RNA splicing factors are essential for the viability of all eukaryotic cells; however, in metazoans some cell types are exquisitely sensitive to disruption of splicing factors, such as neuronal cells which can lead to neurodegenerative diseases. The basis for this tissue selectivity is not well understood due to difficulties in analyzing the consequences of splicing factor defects in whole animal systems. Here, we use zebrafish mutants to show that loss of spliceosomal components, including splicing factor 3b, subunit 1 (sf3b1), caused increased DNA double-strand breaks and apoptosis in embryonic neurons with a concomitant accumulation of R-loops, which are non-canonical nucleic acid structures that promote genomic instability...
January 29, 2018: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29415178/the-sm-core-mediates-the-retention-of-partially-assembled-spliceosomal-snrnps-in-cajal-bodies-until-their-full-maturation
#5
Adriana Roithová, Klára Klimešová, Josef Pánek, Cindy L Will, Reinhard Lührmann, David Stanek, Cyrille Girard
Cajal bodies (CBs) are nuclear non-membrane bound organelles where small nuclear ribonucleoprotein particles (snRNPs) undergo their final maturation and quality control before they are released to the nucleoplasm. However, the molecular mechanism how immature snRNPs are targeted and retained in CBs has yet to be described. Here, we microinjected and expressed various snRNA deletion mutants as well as chimeric 7SK, Alu or bacterial SRP non-coding RNAs and provide evidence that Sm and SMN binding sites are necessary and sufficient for CB localization of snRNAs...
February 5, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29407375/behind-the-scenes-of-hiv-1-replication-alternative-splicing-as-the-dependency-factor-on-the-quiet
#6
REVIEW
Helene Sertznig, Frank Hillebrand, Steffen Erkelenz, Heiner Schaal, Marek Widera
Alternative splicing plays a key role in the HIV-1 life cycle and is essential to maintain an equilibrium of mRNAs that encode viral proteins and polyprotein-isoforms. In particular, since all early HIV-1 proteins are expressed from spliced intronless and late enzymatic and structural proteins from intron containing, i.e. splicing repressed viral mRNAs, cellular splicing factors and splicing regulatory proteins are crucial for the replication capacity. In this review, we will describe the complex network of cis-acting splicing regulatory elements (SREs), which are mainly localized in the neighbourhoods of all HIV-1 splice sites and warrant the proper ratio of individual transcript isoforms...
January 29, 2018: Virology
https://www.readbyqxmd.com/read/29391529/small-molecule-flunarizine-increases-smn-protein-in-nuclear-cajal-bodies-and-motor-function-in-a-mouse-model-of-spinal-muscular-atrophy
#7
Delphine Sapaly, Matthieu Dos Santos, Perrine Delers, Olivier Biondi, Gwendoline Quérol, Léo Houdebine, Kevinee Khoobarry, François Girardet, Philippe Burlet, Anne-Sophie Armand, Christophe Chanoine, Jean-François Bureau, Frédéric Charbonnier, Suzie Lefebvre
The hereditary neurodegenerative disorder spinal muscular atrophy (SMA) is characterized by the loss of spinal cord motor neurons and skeletal muscle atrophy. SMA is caused by mutations of the survival motor neuron (SMN) gene leading to a decrease in SMN protein levels. The SMN deficiency alters nuclear body formation and whether it can contribute to the disease remains unclear. Here we screen a series of small-molecules on SMA patient fibroblasts and identify flunarizine that accumulates SMN into Cajal bodies, the nuclear bodies important for the spliceosomal small nuclear RNA (snRNA)-ribonucleoprotein biogenesis...
February 1, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29390077/cwc23-is-a-component-of-the-ntr-complex-and-functions-to-stabilize-ntr1-and-facilitate-disassembly-of-spliceosome-intermediates
#8
Yu-Lun Su, Hsin-Chou Chen, Rong-Tzong Tsai, Pei-Chun Lin, Soo-Chen Cheng
Cwc23 is a member of the J protein family, and has been shown to interact with Ntr1, a scaffold protein that interacts with Ntr2 and Prp43 to form the NTR complex that mediates spliceosome disassembly. We show that Cwc23 is also an intrinsic component of the NTR complex, and that it interacts with the carboxyl terminus of Ntr1. Metabolic depletion of Cwc23 concurrently depleted Ntr1 and Ntr2, suggesting a role for Cwc23 in stabilizing these two proteins. Ntr1, Ntr2 and Cwc23 are stoichiometrically balanced, and form a stable heterotrimer...
January 30, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29377672/molecular-mechanism-and-evolution-of-nuclear-pre-mrna-and-group-ii-intron-splicing-insights-from-cryo-electron-microscopy-structures
#9
Wojciech P Galej, Navtej Toor, Andrew J Newman, Kiyoshi Nagai
Nuclear pre-mRNA splicing and group II intron self-splicing both proceed by two-step transesterification reactions via a lariat intron intermediate. Recently determined cryo-electron microscopy (cryo-EM) structures of catalytically active spliceosomes revealed the RNA-based catalytic core and showed how pre-mRNA substrates and reaction products are positioned in the active site. These findings highlight a strong structural similarity to the group II intron active site, strengthening the notion that group II introns and spliceosomes evolved from a common ancestor...
January 29, 2018: Chemical Reviews
https://www.readbyqxmd.com/read/29367453/the-life-of-u6-small-nuclear-rna-from-cradle-to-grave
#10
Allison L Didychuk, Samuel E Butcher, David A Brow
Removal of introns from precursor messenger RNA (pre-mRNA) and some non-coding transcripts is an essential step in eukaryotic gene expression. In the nucleus, this process of RNA splicing is carried out by the spliceosome, a multi-megaDalton macromolecular machine whose core components are conserved from yeast to humans. In addition to many proteins, the spliceosome contains five uridine-rich small nuclear RNAs (snRNAs) that undergo an elaborate series of conformational changes to correctly recognize the splice sites and catalyze intron removal...
January 24, 2018: RNA
https://www.readbyqxmd.com/read/29367434/proteomics-profiling-of-cll-versus-healthy-b-cells-identifies-putative-therapeutic-targets-and-a-subtype-independent-signature-of-spliceosome-dysregulation
#11
Harvey E Johnston, Matthew John Carter, Marta Larrayoz, James Clarke, Spiros D Garbis, David Oscier, Jonathan C Strefford, Andrew J Steele, Renata Walewska, Mark S Cragg
Chronic lymphocytic leukaemia (CLL) is a heterogeneous B-cell cancer exhibiting a wide spectrum of disease courses and treatment responses. Molecular characterisation of RNA and DNA from CLL cases has led to the identification of important driver mutations and disease sub-types, but the precise mechanisms of disease progression remain elusive. To further our understanding of CLL biology we performed isobaric labelling and mass spectrometry proteomics on 14 CLL samples, comparing them with B-cells from healthy donors (HDB)...
January 24, 2018: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/29365392/-gene-mutations-from-511-myelodysplastic-syndromes-patients-performed-by-targeted-gene-sequencing
#12
B Li, J Y Wang, J Q Liu, Z X Shi, S L Peng, H J Huang, T J Qin, Z F Xu, Y Zhang, L W Fang, H L Zhang, N B Hu, L J Pan, S Q Qu, Z J Xiao
Objective: To study the characteristics of gene mutations in Chinese myelodysplastic syndromes (MDS) patients. Methods: A total of 511 Chinese patients with MDS performed 112-gene targeted sequencing were retrospectively analyzed. Results: Eighty-three distinct mutant genes were found in 511 patients with MDS. Amongst these, the most frequent mutations was associated with epigenetics (50%) , followed by spliceosome (37%) , signal transduction (34%) , transcription factors (24%) and cell cycle/apoptosis (17%) ...
December 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/29365324/expression-profiling-of-snornas-in-normal-hematopoiesis-and-aml
#13
Wayne A Warner, David H Spencer, Maria Trissal, Brian S White, Nichole Helton, Timothy J Ley, Daniel C Link
Small nucleolar RNAs (snoRNAs) are noncoding RNAs that contribute to ribosome biogenesis and RNA splicing by modifying ribosomal RNA and spliceosome RNAs, respectively. We optimized a next-generation sequencing approach and a custom analysis pipeline to identify and quantify expression of snoRNAs in acute myeloid leukemia (AML) and normal hematopoietic cell populations. We show that snoRNAs are expressed in a lineage- and development-specific fashion during hematopoiesis. The most striking examples involve snoRNAs located in 2 imprinted loci, which are highly expressed in hematopoietic progenitors and downregulated during myeloid differentiation...
January 23, 2018: Blood Advances
https://www.readbyqxmd.com/read/29363793/signature-micrornas-of-nuclear-sm-complex-associated-with-breast-cancer-tumorigenesis
#14
Xinyi Zhang, Bo Shen, Yalei Cui
It is well known that Sm proteins, small nuclear ribonucleoproteins, act as core spliceosomal factors in alternative splicing of mRNA precursors. MicroRNAs (miRNAs) can function in alternative splicing by targeting mRNAs of splicing factors. However, the direct interaction between miRNAs and proteins of splicing complex in nucleus has not been explored. In this study, the mature miRNAs in nuclear Sm complex of breast cancer cells and normal breast epithelial cells were characterized. Small RNA sequencing of immunoprecipitated nuclear Sm complex with the SmD1-specific antibody identified 123 and 170 mature miRNAs in nuclear Sm complex of normal breast cells and breast cancer cells, respectively...
January 24, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29361316/structure-and-conformational-dynamics-of-the-human-spliceosomal-bact-complex
#15
David Haselbach, Ilya Komarov, Dmitry E Agafonov, Klaus Hartmuth, Benjamin Graf, Olexandr Dybkov, Henning Urlaub, Berthold Kastner, Reinhard Lührmann, Holger Stark
The spliceosome is a highly dynamic macromolecular complex that precisely excises introns from pre-mRNA. Here we report the cryo-EM 3D structure of the human Bact spliceosome at 3.4 Å resolution. In the Bact state, the spliceosome is activated but not catalytically primed, so that it is functionally blocked prior to the first catalytic step of splicing. The spliceosomal core is similar to the yeast Bact spliceosome; important differences include the presence of the RNA helicase aquarius and peptidyl prolyl isomerases...
January 12, 2018: Cell
https://www.readbyqxmd.com/read/29360106/structure-of-the-human-activated-spliceosome-in-three-conformational-states
#16
Xiaofeng Zhang, Chuangye Yan, Xiechao Zhan, Lijia Li, Jianlin Lei, Yigong Shi
During each cycle of pre-mRNA splicing, the pre-catalytic spliceosome (B complex) is converted into the activated spliceosome (Bact complex), which has a well-formed active site but cannot proceed to the branching reaction. Here, we present the cryo-EM structure of the human Bact complex in three distinct conformational states. The EM map allows atomic modeling of nearly all protein components of the U2 small nuclear ribonucleoprotein (snRNP), including three of the SF3a complex and seven of the SF3b complex...
January 23, 2018: Cell Research
https://www.readbyqxmd.com/read/29355515/spliceosome-associated-protein-130-exacerbates-alcohol-induced-liver-injury-by-inducing-nlrp3-inflammasome-mediated-il1%C3%AE-in-mice
#17
Jong Won Kim, Yoon-Seok Roh, Hyeneui Jeong, Ho-Keun Yi, Min-Ho Lee, Chae Woong Lim, Bumseok Kim
Excessive alcohol consumption leads to chronic liver diseases. Macrophage-inducible C-type lectin (Mincle) is a C-type lectin receptor that recognizes spliceosome-associated protein 130 (SAP130) known as an endogenous ligand released from dying cells. Our aim was to examine the role of Mincle-SAP130 in the pathogenesis of alcoholic liver disease. Alcohol-induced liver injury was induced in wild-type (WT) and Mincle knout-out (KO) mice using a chronic-binge ethanol-feeding model. Mincle KO mice showed significant lower hepatic steatosis, inflammation with neutrophil infiltration, and fibrosis compared to WT mice after alcohol feeding...
January 16, 2018: American Journal of Pathology
https://www.readbyqxmd.com/read/29351963/the-exon-junction-complex-structural-insights-into-a-faithful-companion-of-mammalian-mrnps
#18
REVIEW
Jennifer V Gerbracht, Niels H Gehring
During splicing, the exon junction complex (EJC) is deposited upstream of exon-exon boundaries. The EJC and its peripheral bound proteins play an essential role in mediating mRNA export, translation and turnover. However, the exact sequence of EJC assembly and the involved factors during splicing remain elusive. Recently published structures of the human C* spliceosome clarified the position of the EJC at this phase of splicing and have given insight into previously unidentified interactions between the EJC and spliceosomal proteins...
January 19, 2018: Biochemical Society Transactions
https://www.readbyqxmd.com/read/29345637/structural-basis-of-rna-polymerase-iii-transcription-initiation
#19
Guillermo Abascal-Palacios, Ewan Phillip Ramsay, Fabienne Beuron, Edward Morris, Alessandro Vannini
RNA polymerase (Pol) III transcribes essential non-coding RNAs, including the entire pool of transfer RNAs, the 5S ribosomal RNA and the U6 spliceosomal RNA, and is often deregulated in cancer cells. The initiation of gene transcription by Pol III requires the activity of the transcription factor TFIIIB to form a transcriptionally active Pol III preinitiation complex (PIC). Here we present electron microscopy reconstructions of Pol III PICs at 3.4-4.0 Å and a reconstruction of unbound apo-Pol III at 3.1 Å...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29338026/flow-cytometric-analysis-identifies-changes-in-s-and-m-phases-as-novel-cell-cycle-alterations-induced-by-the-splicing-inhibitor-isoginkgetin
#20
Erin J Vanzyl, Kayleigh R C Rick, Alex B Blackmore, Erin M MacFarlane, Bruce C McKay
The spliceosome is a large ribonucleoprotein complex that catalyzes the removal of introns from RNA polymerase II-transcribed RNAs. Spliceosome assembly occurs in a stepwise manner through specific intermediates referred to as pre-spliceosome complexes E, A, B, B* and C. It has been reported that small molecule inhibitors of the spliceosome that target the SF3B1 protein component of complex A lead to the accumulation of cells in the G1 and G2/M phases of the cell cycle. Here we performed a comprehensive flow cytometry analysis of the effects of isoginkgetin (IGG), a natural compound that interferes with spliceosome assembly at a later step, complex B formation...
2018: PloS One
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