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https://www.readbyqxmd.com/read/27909216/molecular-determinants-of-pathogenesis-and-clinical-phenotype-in-myeloproliferative-neoplasms
#1
Jacob Grinfeld, Jyoti Nangalia, Anthony R Green
The myeloproliferative neoplasms are a heterogeneous group of clonal disorders characterised by overproduction of mature cells in the peripheral blood, together with an increased risk of thrombosis and progression to acute myeloid leukemia. The majority of patients with Philadelphia-chromosome negative myeloproliferative neoplasms harbour somatic mutations in Janus kinase 2, leading to constitutive activation. Acquired mutations in calreticulin or myeloproliferative leukemia virus oncogene are found in a significant number of patients with essential thrombocythaemia or myelofibrosis, and mutations in numerous epigenetic regulators and spliceosome components are also seen...
December 1, 2016: Haematologica
https://www.readbyqxmd.com/read/27907902/active-5-splice-sites-regulate-the-biogenesis-efficiency-of-arabidopsis-micrornas-derived-from-intron-containing-genes
#2
Katarzyna Knop, Agata Stepien, Maria Barciszewska-Pacak, Michal Taube, Dawid Bielewicz, Michal Michalak, Jan W Borst, Artur Jarmolowski, Zofia Szweykowska-Kulinska
Arabidopsis, miR402 that is encoded within the first intron of a protein-coding gene At1g77230, is induced by heat stress. Its upregulation correlates with splicing inhibition and intronic proximal polyA site selection. It suggests that miR402 is not processed from an intron, but rather from a shorter transcript after selection of the proximal polyA site within this intron. Recently, introns and active 5' splice sites (5'ss') have been shown to stimulate the accumulation of miRNAs encoded within the first exons of intron-containing MIR genes...
October 5, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27905398/structure-of-the-rbm7-zcchc8-core-of-the-next-complex-reveals-connections-to-splicing-factors
#3
Sebastian Falk, Ksenia Finogenova, Mireille Melko, Christian Benda, Søren Lykke-Andersen, Torben Heick Jensen, Elena Conti
The eukaryotic RNA exosome participates extensively in RNA processing and degradation. In human cells, three accessory factors (RBM7, ZCCHC8 and hMTR4) interact to form the nuclear exosome targeting (NEXT) complex, which directs a subset of non-coding RNAs for exosomal degradation. Here we elucidate how RBM7 is incorporated in the NEXT complex. We identify a proline-rich segment of ZCCHC8 as the interaction site for the RNA-recognition motif (RRM) of RBM7 and present the crystal structure of the corresponding complex at 2...
December 1, 2016: Nature Communications
https://www.readbyqxmd.com/read/27899647/spliceosomal-protein-eftud2-mutation-leads-to-p53-dependent-apoptosis-in-zebrafish-neural-progenitors
#4
Lei Lei, Shou-Yu Yan, Ran Yang, Jia-Yu Chen, Yumei Li, Ye Bu, Nannan Chang, Qinchao Zhou, Xiaojun Zhu, Chuan-Yun Li, Jing-Wei Xiong
Haploinsufficiency of EFTUD2 (Elongation Factor Tu GTP Binding Domain Containing 2) is linked to human mandibulofacial dysostosis, Guion-Almeida type (MFDGA), but the underlying cellular and molecular mechanisms remain to be addressed. We report here the isolation, cloning and functional analysis of the mutated eftud2 (snu114) in a novel neuronal mutant fn10a in zebrafish. This mutant displayed abnormal brain development with evident neuronal apoptosis while the development of other organs appeared less affected...
November 28, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27894420/structural-basis-for-the-recognition-of-spliceosomal-smn-b-b-proteins-by-the-rbm5-ocre-domain-in-splicing-regulation
#5
André Mourão, Sophie Bonnal, Komal Soni, Lisa Warner, Rémy Bordonné, Juan Valcárcel, Michael Sattler
The multi-domain splicing factor RBM5 regulates the balance between antagonistic isoforms of the apoptosis-control genes FAS/CD95, Caspase-2 and AID. An OCRE (OCtamer REpeat of aromatic residues) domain found in RBM5 is important for alternative splicing regulation and mediates interactions with components of the U4/U6.U5 tri-snRNP. We show that the RBM5 OCRE domain adopts a unique β-sheet fold. NMR and biochemical experiments demonstrate that the OCRE domain directly binds to the proline-rich C-terminal tail of the essential snRNP core proteins SmN/B/B'...
November 29, 2016: ELife
https://www.readbyqxmd.com/read/27882870/large-scale-remodeling-of-a-repressed-exon-ribonucleoprotein-to-an-exon-definition-complex-active-for-splicing
#6
Somsakul Pop Wongpalee, Ajay Vashisht, Shalini Sharma, Darryl Chui, James A Wohlschlegel, Douglas L Black
Polypyrimidine-tract binding protein PTBP1 can repress splicing during the exon definition phase of spliceosome assembly, but the assembly steps leading to an exon definition complex (EDC) and how PTBP1 might modulate them are not clear. We found that PTBP1 binding in the flanking introns allowed normal U2AF and U1 snRNP binding to the target exon splice sites but blocked U2 snRNP assembly in HeLa nuclear extract. Characterizing a purified PTBP1-repressed complex, as well as an active early complex and the final EDC by SILAC-MS, we identified extensive PTBP1-modulated changes in exon RNP composition...
November 24, 2016: ELife
https://www.readbyqxmd.com/read/27881601/structural-basis-for-snrna-recognition-by-the-double-wd40-repeat-domain-of-gemin5
#7
Wenxing Jin, Yi Wang, Chao-Pei Liu, Na Yang, Mingliang Jin, Yao Cong, Mingzhu Wang, Rui-Ming Xu
Assembly of the spliceosomal small nuclear ribonucleoparticle (snRNP) core requires the participation of the multisubunit SMN (survival of motor neuron) complex, which contains SMN and several Gemin proteins. The SMN and Gemin2 subunits directly bind Sm proteins, and Gemin5 is required for snRNP biogenesis and has been implicated in snRNA recognition. The RNA sequence required for snRNP assembly includes the Sm site and an adjacent 3' stem-loop, but a precise understanding of Gemin5's RNA-binding specificity is lacking...
November 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27880071/interplay-of-cis-and-trans-regulatory-mechanisms-in-the-spliceosomal-rna-helicase-brr2
#8
Eva Absmeier, Christian Becke, Jan Wollenhaupt, Karine F Santos, Markus C Wahl
RNA helicase Brr2 is implicated in multiple phases of pre-mRNA splicing and thus requires tight regulation. Brr2 can be auto-inhibited via a large N-terminal region folding back onto its helicase core and auto-activated by a catalytically inactive C-terminal helicase cassette. Furthermore, it can be regulated in trans by the Jab1 domain of the Prp8 protein, which can inhibit Brr2 by intermittently inserting a C-terminal tail in the enzyme's RNA-binding tunnel or activate the helicase after removal of this tail...
November 23, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27875300/the-fission-yeast-pre-mrna-processing-factor-18-prp18-has-intron-specific-splicing-functions-with-links-to-g1-s-cell-cycle-progression
#9
Nagampalli Vijaykrishna, Geetha Melangath, Rakesh Kumar, Piyush Khandelia, Pushpinder Bawa, Raghavan Varadarajan, Usha Vijayraghavan
The fission yeast genome which contains numerous short introns is an apt model for studies on fungal splicing mechanisms and splicing by intron-definition. Here we perform a domain analysis of the evolutionarily conserved Schizosaccharomyces pombe pre-mRNA processing factor, SpPrp18. Our mutational and biophysical analyses of the C- terminal alpha-helical bundle reveal critical roles for the conserved region as well as and helix five. We generate a novel conditional missense mutant, spprp18-5 To assess the role of SpPrp18, we performed global splicing analyses on cells depleted of prp18+ and the conditional spprp18-5 mutant which show widespread but intron-specific defects...
November 15, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27873472/perfect-timing-splicing-and-transcription-rates-in-living-cells
#10
REVIEW
Tara Alpert, Lydia Herzel, Karla M Neugebauer
An important step toward understanding gene regulation is the elucidation of the time necessary for the completion of individual steps. Measurement of reaction rates can reveal potential nodes for regulation. For example, measurements of in vivo transcription elongation rates reveal regulation by DNA sequence, gene architecture, and chromatin. Pre-mRNA splicing is regulated by transcription elongation rates and vice versa, yet the rates of RNA processing reactions remain largely elusive. Since the 1980s, numerous model systems and approaches have been used to determine the precise timing of splicing in vivo...
November 21, 2016: Wiley Interdisciplinary Reviews. RNA
https://www.readbyqxmd.com/read/27864674/interactions-between-giardia-duodenalis-sm-proteins-and-their-association-with-spliceosomal-snrnas
#11
Vanessa Gómez, Moisés Wasserman
Giardia duodenalis is a parasite that colonises the intestines of humans and other vertebrates, causing diarrhoea and poor nutrient absorption. G. duodenalis is sometimes considered an early diverging eukaryote, and its genome exhibits simplified molecular machinery for many cellular processes, which makes it an interesting model to study. The spliceosome, one of the most complex molecular machines in the eukaryotic cell, is responsible for intron excision and exon splicing. Just over a decade ago, it was believed that the G...
November 18, 2016: Parasitology Research
https://www.readbyqxmd.com/read/27863452/mutation-in-non-coding-rna-rnu12-causes-early-onset-cerebellar-ataxia
#12
Mahmoud Fawzi Elsaid, Nader Chalhoub, Tawfeg Ben-Omran, Pankaj Kumar, Hussein Kamel, Khalid Ibrahim, Yasmin Mohamoud, Eman Al-Dous, Iman Al-Azwani, Joel A Malek, Karsten Suhre, M Elizabeth Ross, Alice Abdel Aleem
OBJECTIVE: Exome sequences account for only 2% of the genome and may overlook mutations causing disease. To obtain a more complete view, whole genome sequencing (WGS) was analyzed in a large consanguineous family in which members displayed autosomal recessively inherited cerebellar ataxia manifesting before two years of age. METHODS: WGS from blood derived gDNA was used for homozygosity mapping and a rare variant search. RNA from isolated blood leukocytes was used for quantitative PCR, RNA sequencing and comparison of the transcriptomes of affected and unaffected family members...
November 18, 2016: Annals of Neurology
https://www.readbyqxmd.com/read/27863087/posttranscriptional-coordination-of-splicing-and-mirna-biogenesis-in-plants
#13
REVIEW
Agata Stepien, Katarzyna Knop, Jakub Dolata, Michal Taube, Mateusz Bajczyk, Maria Barciszewska-Pacak, Andrzej Pacak, Artur Jarmolowski, Zofia Szweykowska-Kulinska
MicroRNAs (miRNAs) are short, single-stranded, noncoding RNAs that play a crucial role in basic physiological and morphological processes and in response to various stresses in eukaryotic organisms. However, the miRNA biogenesis, which is based on the action of complex protein machinery, varies between plants and animals, with the differences largely concerning the location of the process, the protein composition of the microprocessor, the mechanism of miRNA action on mRNA target, and the miRNA gene ( MIR ) structure...
November 9, 2016: Wiley Interdisciplinary Reviews. RNA
https://www.readbyqxmd.com/read/27862552/solution-structure-of-the-first-rna-recognition-motif-domain-of-human-spliceosomal-protein-sf3b49-and-its-mode-of-interaction-with-a-sf3b145-fragment
#14
Kanako Kuwasako, Nobukazu Nameki, Kengo Tsuda, Mari Takahashi, Atsuko Sato, Naoya Tochio, Makoto Inoue, Takaho Terada, Takanori Kigawa, Naohiro Kobayashi, Mikako Shirouzu, Takuhiro Ito, Taiichi Sakamoto, Kaori Wakamatsu, Peter Güntert, Seizo Takahashi, Shigeyuki Yokoyama, Yutaka Muto
The spliceosomal protein SF3b49, a component of the splicing factor 3b (SF3b) protein complex in the U2 small nuclear ribonucleoprotein, contains two RNA recognition motif (RRM) domains. In yeast, the first RRM domain (RRM1) of Hsh49 protein (yeast orthologue of human SF3b49) reportedly interacts with another component, Cus1 protein (orthologue of human SF3b145). Here, we solved the solution structure of the RRM1 of human SF3b49 and examined its mode of interaction with a fragment of human SF3b145 using NMR methods...
November 16, 2016: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/27858508/activation-of-transcription-enforces-the-formation-of-distinct-nuclear-bodies-in-zebrafish-embryos
#15
Patricia Heyn, Hanna Salmonowicz, Jonathan Rodenfels, Karla M Neugebauer
Nuclear bodies are cellular compartments that lack lipid bilayers and harbor specific RNAs and proteins. Recent proposals that nuclear bodies form through liquid-liquid phase separation leave the question of how different nuclear bodies maintain their distinct identities unanswered. Here we investigate Cajal bodies (CBs), histone locus bodies (HLBs) and nucleoli - involved in assembly of the splicing machinery, histone mRNA 3' end processing, and rRNA processing, respectively - in the embryos of the zebrafish, Danio rerio...
November 18, 2016: RNA Biology
https://www.readbyqxmd.com/read/27852923/unmasking-the-u2af-homology-motif-family-a-bona-fide-protein-protein-interaction-motif-in-disguise
#16
REVIEW
Sarah Loerch, Clara L Kielkopf
U2AF homology motifs (UHM) that recognize U2AF ligand motifs (ULM) are an emerging family of protein-protein interaction modules. UHM-ULM interactions recur in pre-mRNA splicing factors including U2AF1 and SF3b1, which are frequently mutated in myelodysplastic syndromes. The core topology of the UHM resembles an RNA recognition motif and is often mistakenly classified within this large family. Here, we unmask the charade and review recent discoveries of UHM-ULM modules for protein-protein interactions. Diverse polypeptide extensions and selective phosphorylation of UHM and ULM family members offer new molecular mechanisms for the assembly of specific partners in the early-stage spliceosome...
December 2016: RNA
https://www.readbyqxmd.com/read/27836865/molecular-pathways-understanding-and-targeting-mutant-spliceosomal-proteins
#17
Akihide Yoshimi, Omar Abdel-Wahab
Splicing of precursor messenger RNA is a critical step in regulating gene expression and major advances are being made in understanding the composition and structure of the enzymatic complex which performs splicing, termed the spliceosome. In parallel, there has been increased appreciation for diverse mechanisms by which alterations in splicing contribute to cancer pathogenesis. Key among these includes change-of-function mutations in genes encoding spliceosomal proteins. Such mutations are amongst the most common genetic alterations in myeloid and lymphoid leukemias, making efforts to therapeutically target cells bearing these mutations critical...
November 10, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27821747/systematic-autoantigen-analysis-identifies-a-distinct-subtype-of-scleroderma-with-coincident-cancer
#18
George J Xu, Ami A Shah, Mamie Z Li, Qikai Xu, Antony Rosen, Livia Casciola-Rosen, Stephen J Elledge
Scleroderma is a chronic autoimmune rheumatic disease associated with widespread tissue fibrosis and vasculopathy. Approximately two-thirds of all patients with scleroderma present with three dominant autoantibody subsets. Here, we used a pair of complementary high-throughput methods for antibody epitope discovery to examine patients with scleroderma with or without known autoantibody specificities. We identified a specificity for the minor spliceosome complex containing RNA Binding Region (RNP1, RNA recognition motif) Containing 3 (RNPC3) that is found in patients with scleroderma without known specificities and is absent in unrelated autoimmune diseases...
November 7, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27818134/transcriptomic-characterization-of-sf3b1-mutation-reveals-its-pleiotropic-effects-in-chronic-lymphocytic-leukemia
#19
Lili Wang, Angela N Brooks, Jean Fan, Youzhong Wan, Rutendo Gambe, Shuqiang Li, Sarah Hergert, Shanye Yin, Samuel S Freeman, Joshua Z Levin, Lin Fan, Michael Seiler, Silvia Buonamici, Peter G Smith, Kevin F Chau, Carrie L Cibulskis, Wandi Zhang, Laura Z Rassenti, Emanuela M Ghia, Thomas J Kipps, Stacey Fernandes, Donald B Bloch, Dylan Kotliar, Dan A Landau, Sachet A Shukla, Jon C Aster, Robin Reed, David S DeLuca, Jennifer R Brown, Donna Neuberg, Gad Getz, Kenneth J Livak, Matthew M Meyerson, Peter V Kharchenko, Catherine J Wu
Mutations in SF3B1, which encodes a spliceosome component, are associated with poor outcome in chronic lymphocytic leukemia (CLL), but how these contribute to CLL progression remains poorly understood. We undertook a transcriptomic characterization of primary human CLL cells to identify transcripts and pathways affected by SF3B1 mutation. Splicing alterations, identified in the analysis of bulk cells, were confirmed in single SF3B1-mutated CLL cells and also found in cell lines ectopically expressing mutant SF3B1...
November 14, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27808266/integrative-omics-connects-n-glycoproteome-wide-alterations-with-pathways-and-regulatory-events-in-induced-pluripotent-stem-cells
#20
Putty-Reddy Sudhir, Madireddy Pavana Kumari, Wei-Ting Hsu, Chein-Hung Chen, Hung-Chih Kuo, Chung-Hsuan Chen
Molecular-level differences ranging from genomes to proteomes, but not N-glycoproteomes, between human induced pluripotent stem cells (hiPSCs) and embryonic stem cells (hESCs) have been assessed to gain insights into cell reprogramming and induced pluripotency. Our multiplexed quantitative N-glycoproteomics study identified altered N-glycoproteins that significantly regulate cell adhesion processes in hiPSCs compared to hESCs. The integrative proteomics and functional network analyses of the altered N-glycoproteins revealed their significant interactions with known PluriNet (pluripotency-associated network) proteins...
November 3, 2016: Scientific Reports
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