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https://www.readbyqxmd.com/read/28549066/alternative-exon-definition-events-control-the-choice-between-nuclear-retention-and-cytoplasmic-export-of-u11-u12-65k-mrna
#1
Jens Verbeeren, Bhupendra Verma, Elina H Niemelä, Karen Yap, Eugene V Makeyev, Mikko J Frilander
Cellular homeostasis of the minor spliceosome is regulated by a negative feed-back loop that targets U11-48K and U11/U12-65K mRNAs encoding essential components of the U12-type intron-specific U11/U12 di-snRNP. This involves interaction of the U11 snRNP with an evolutionarily conserved splicing enhancer giving rise to unproductive mRNA isoforms. In the case of U11/U12-65K, this mechanism controls the length of the 3' untranslated region (3'UTR). We show that this process is dynamically regulated in developing neurons and some other cell types, and involves a binary switch between translation-competent mRNAs with a short 3'UTR to non-productive isoforms with a long 3'UTR that are retained in the nucleus or/and spliced to the downstream amylase locus...
May 26, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28530653/structure-of-a-pre-catalytic-spliceosome
#2
Clemens Plaschka, Pei-Chun Lin, Kiyoshi Nagai
Intron removal requires assembly of the spliceosome on pre-mRNA and extensive remodelling to form the spliceosome's catalytic centre. Here we report the cryo-electron microscopy structure of the yeast pre-catalytic B complex spliceosome at near-atomic resolution. The mobile U2 snRNP associates with U4/U6.U5 tri-snRNP through U2/U6 helix II and an interface between U4/U6 di-snRNP and the U2 snRNP SF3b-containing domain, which also transiently contacts the helicase Brr2. The U2 snRNP 3' region is flexibly attached to the SF3b-containing domain and protrudes over the concave surface of tri-snRNP, where the U1 snRNP may reside before its release from the pre-mRNA 5'-splice site...
May 22, 2017: Nature
https://www.readbyqxmd.com/read/28515487/functional-interaction-between-fus-and-smn-underlies-sma-like-splicing-changes-in-wild-type-hfus-mice
#3
Alessia Mirra, Simona Rossi, Silvia Scaricamazza, Michela Di Salvio, Illari Salvatori, Cristiana Valle, Paola Rusmini, Angelo Poletti, Gianluca Cestra, Maria Teresa Carrì, Maur O Cozzolino
Several of the identified genetic factors in Amyotrophic Lateral Sclerosis (ALS) point to dysfunction in RNA processing as a major pathogenic mechanism. However, whether a precise RNA pathway is particularly affected remains unknown. Evidence suggests that FUS, that is mutated in familial ALS, and SMN, the causative factor in Spinal Muscular Atrophy (SMA), cooperate to the same molecular pathway, i.e. regulation of alternative splicing, and that disturbances in SMN-regulated functions, either caused by depletion of SMN protein (as in the case of SMA) or by pathogenic interactions between FUS and SMN (as in the case of ALS) might be a common theme in both diseases...
May 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28515276/assembly-of-the-u5-snrnp-component-prpf8-is-controlled-by-the-hsp90-r2tp-chaperones
#4
Anna Malinová, Zuzana Cvačková, Daniel Matějů, Zuzana Hořejší, Claire Abéza, Franck Vandermoere, Edouard Bertrand, David Staněk, Céline Verheggen
Splicing is catalyzed by the spliceosome, a complex of five major small nuclear ribonucleoprotein particles (snRNPs). The pre-mRNA splicing factor PRPF8 is a crucial component of the U5 snRNP, and together with EFTUD2 and SNRNP200, it forms a central module of the spliceosome. Using quantitative proteomics, we identified assembly intermediates containing PRPF8, EFTUD2, and SNRNP200 in association with the HSP90/R2TP complex, its ZNHIT2 cofactor, and additional proteins. HSP90 and R2TP bind unassembled U5 proteins in the cytoplasm, stabilize them, and promote the formation of the U5 snRNP...
May 17, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28502770/an-atomic-structure-of-the-human-spliceosome
#5
Xiaofeng Zhang, Chuangye Yan, Jing Hang, Lorenzo I Finci, Jianlin Lei, Yigong Shi
Mechanistic understanding of pre-mRNA splicing requires detailed structural information on various states of the spliceosome. Here we report the cryo electron microscopy (cryo-EM) structure of the human spliceosome just before exon ligation (the C(∗) complex) at an average resolution of 3.76 Å. The splicing factor Prp17 stabilizes the active site conformation. The step II factor Slu7 adopts an extended conformation, binds Prp8 and Cwc22, and is poised for selection of the 3'-splice site. Remarkably, the intron lariat traverses through a positively charged central channel of RBM22; this unusual organization suggests mechanisms of intron recruitment, confinement, and release...
May 18, 2017: Cell
https://www.readbyqxmd.com/read/28500052/exploring-the-impact-of-cleavage-and-polyadenylation-factors-on-pre-mrna-splicing-across-eukaryotes
#6
Gildas Lepennetier, Francesco Catania
In human, mouse and Drosophila, the spliceosomal complex U1 snRNP (U1) protects transcripts from premature cleavage and polyadenylation at proximal intronic polyadenylation signals (PAS). These U1-mediated effects preserve transcription integrity and are known as telescripting. The watchtower role of U1 throughout transcription is clear. What is less clear is whether cleavage and polyadenylation factors (CPFs) are simply patrolled or if they may actively antagonize U1 recruitment. In addressing this question, we found that in the introns of human, mouse and Drosophila and of 14 other eukaryotes, including multi- and single-celled species, the conserved AATAAA PAS - a major target for CPFs - is selected against...
May 12, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28482101/environment-dependent-regulation-of-spliceosome-activity-by-the-lsm2-8-complex-in-arabidopsis
#7
Cristian Carrasco-López, Tamara Hernández-Verdeja, Carlos Perea-Resa, David Abia, Rafael Catalá, Julio Salinas
Spliceosome activity is tightly regulated to ensure adequate splicing in response to internal and external cues. It has been suggested that core components of the spliceosome, such as the snRNPs, would participate in the control of its activity. The experimental indications supporting this proposition, however, remain scarce, and the operating mechanisms poorly understood. Here, we present genetic and molecular evidence demonstrating that the LSM2-8 complex, the protein moiety of the U6 snRNP, regulates the spliceosome activity in Arabidopsis, and that this regulation is controlled by the environmental conditions...
May 8, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28446664/analysis-of-competing-hiv-1-splice-donor-sites-uncovers-a-tight-cluster-of-splicing-regulatory-elements-within-exon-2-2b
#8
Anna-Lena Brillen, Lara Walotka, Frank Hillebrand, Lisa Müller, Marek Widera, Stephan Theiss, Heiner Schaal
The HIV-1 accessory protein Vif is essential for viral replication by counteracting the host restriction factor APOBEC3G (A3G), and balanced levels of both proteins are required for efficient viral replication. Non-coding exons 2/2b contain the Vif start codon between their alternatively used splice donors 2 and 2b (D2 and D2b). For the vif mRNA, intron 1 must be removed, while intron 2 must be retained. Thus, splice acceptor 1 (A1) must be activated by U1 snRNP binding to either D2 or D2b, while splicing at D2 or D2b must be prevented...
April 26, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28446598/the-histone-variant-h2a-z-promotes-efficient-cotranscriptional-splicing-in-s-cerevisiae
#9
Lauren T Neves, Stephen Douglass, Roberto Spreafico, Srivats Venkataramanan, Tracy L Kress, Tracy L Johnson
In eukaryotes, a dynamic ribonucleic protein machine known as the spliceosome catalyzes the removal of introns from premessenger RNA (pre-mRNA). Recent studies show the processes of RNA synthesis and RNA processing to be spatio-temporally coordinated, indicating that RNA splicing takes place in the context of chromatin. H2A.Z is a highly conserved histone variant of the canonical histone H2A. In Saccharomyces cerevisiae, H2A.Z is deposited into chromatin by the SWR-C complex, is found near the 5' ends of protein-coding genes, and has been implicated in transcription regulation...
April 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28445500/sf3b1-is-a-stress-sensitive-splicing-factor-that-regulates-both-hsf1-concentration-and-activity
#10
Karen S Kim Guisbert, Eric Guisbert
The heat shock response (HSR) is a well-conserved, cytoprotective stress response that activates the HSF1 transcription factor. During severe stress, cells inhibit mRNA splicing which also serves a cytoprotective function via inhibition of gene expression. Despite their functional interconnectedness, there have not been any previous reports of crosstalk between these two pathways. In a genetic screen, we identified SF3B1, a core component of the U2 snRNP subunit of the spliceosome, as a regulator of the heat shock response in Caenorhabditis elegans...
2017: PloS One
https://www.readbyqxmd.com/read/28431135/reconstitution-of-a-functional-7sk-snrnp
#11
John E Brogie, David H Price
The 7SK small nuclear ribonucleoprotein (snRNP) plays a central role in RNA polymerase II elongation control by regulating the availability of active P-TEFb. We optimized conditions for analyzing 7SK RNA by SHAPE and demonstrated a hysteretic effect of magnesium on 7SK folding dynamics including a 7SK GAUC motif switch. We also found evidence that the 5΄ end pairs alternatively with two different regions of 7SK giving rise to open and closed forms that dictate the state of the 7SK motif. We then used recombinant P-TEFb, HEXIM1, LARP7 and MEPCE to reconstruct a functional 7SK snRNP in vitro...
April 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28426094/sirt7-dependent-deacetylation-of-cdk9-activates-rna-polymerase-ii-transcription
#12
Maximilian F Blank, Sifan Chen, Fabian Poetz, Martina Schnölzer, Renate Voit, Ingrid Grummt
SIRT7 is an NAD+-dependent protein deacetylase that regulates cell growth and proliferation. Previous studies have shown that SIRT7 is required for RNA polymerase I (Pol I) transcription and pre-rRNA processing. Here, we took a proteomic approach to identify novel molecular targets and characterize the role of SIRT7 in non-nucleolar processes. We show that SIRT7 interacts with numerous proteins involved in transcriptional regulation and RNA metabolism, the majority of interactions requiring ongoing transcription...
March 17, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28392442/protein-arginine-methylation-of-npl3-promotes-splicing-of-the-sus1-intron-harboring-non-consensus-5-splice-site-and-branch-site
#13
Bhavana Muddukrishna, Christopher A Jackson, Michael C Yu
Protein arginine methylation occurs on spliceosomal components and spliceosome-associated proteins, but how this modification contributes to their function in pre-mRNA splicing remains sparse. Here we provide evidence that protein arginine methylation of the yeast SR-/hnRNP-like protein Npl3 plays a role in facilitating efficient splicing of the SUS1 intron that harbors a non-consensus 5' splice site and branch site. In yeast cells lacking the major protein arginine methyltransferase HMT1, we observed a change in the co-transcriptional recruitment of the U1 snRNP subunit Snp1 and Npl3 to pre-mRNAs harboring both consensus (ECM33 and ASC1) and non-consensus (SUS1) 5' splice site and branch site...
June 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28379520/sumo-conjugation-to-spliceosomal-proteins-is-required-for-efficient-pre-mrna-splicing
#14
Berta Pozzi, Laureano Bragado, Cindy L Will, Pablo Mammi, Guillermo Risso, Henning Urlaub, Reinhard Lührmann, Anabella Srebrow
Pre-mRNA splicing is catalyzed by the spliceosome, a multi-megadalton ribonucleoprotein machine. Previous work from our laboratory revealed the splicing factor SRSF1 as a regulator of the SUMO pathway, leading us to explore a connection between this pathway and the splicing machinery. We show here that addition of a recombinant SUMO-protease decreases the efficiency of pre-mRNA splicing in vitro. By mass spectrometry analysis of anti-SUMO immunoprecipitated proteins obtained from purified splicing complexes formed along the splicing reaction, we identified spliceosome-associated SUMO substrates...
March 30, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28379354/motor-neuronal-repletion-of-the-nmj-organizer-agrin-modulates-the-severity-of-the-spinal-muscular-atrophy-disease-phenotype-in-model-mice
#15
Jeong-Ki Kim, Charlotte Caine, Tomoyuki Awano, Ruth Herbst, Umrao R Monani
Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure...
March 31, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28348170/crystal-structure-of-u2-snrnp-sf3b-components-hsh49p-in-complex-with-cus1p-binding-domain
#16
Anne-Marie A M van Roon, Chris Oubridge, Eiji Obayashi, Benedetta Sposito, Andrew James Newman, Bertrand Seraphin, Kiyoshi Nagai
Spliceosomal proteins Hsh49p and Cus1p are components of SF3b, which together with SF3a, Msl1p/Lea1p, Sm proteins and U2 snRNA, form U2 snRNP, which plays a crucial role in pre-mRNA splicing. Hsh49p, comprising two RRMs, forms a heterodimer with Cus1p. We determined the crystal structures of Saccharomyces cerevisiae full-length Hsh49p as well as its RRM1 in complex with a minimal binding region of Cus1p (residues 290-368). The structures show that the Cus1 fragment binds to the α-helical surface of Hsh49p RRM1, opposite the four-stranded β-sheet, leaving the canonical RNA binding surface available to bind RNA...
March 27, 2017: RNA
https://www.readbyqxmd.com/read/28335716/human-mfap1-is-a-cryptic-ortholog-of-the-saccharomyces-cerevisiae-spp381-splicing-factor
#17
Alexander K C Ulrich, Markus C Wahl
BACKGROUND: Pre-mRNA splicing involves the stepwise assembly of a pre-catalytic spliceosome, followed by its catalytic activation, splicing catalysis and disassembly. Formation of the pre-catalytic spliceosomal B complex involves the incorporation of the U4/U6.U5 tri-snRNP and of a group of non-snRNP B-specific proteins. While in Saccharomyces cerevisiae the Prp38 and Snu23 proteins are recruited as components of the tri-snRNP, metazoan orthologs of Prp38 and Snu23 associate independently of the tri-snRNP as members of the B-specific proteins...
March 24, 2017: BMC Evolutionary Biology
https://www.readbyqxmd.com/read/28302904/pharmacological-inhibition-of-the-spliceosome-subunit-sf3b-triggers-ejc-independent-nmd
#18
Teresa Carvalho, Sandra Martins, José Rino, Sérgio Marinho, Maria Carmo-Fonseca
Spliceostatin A, meayamycin, and pladienolide B are small molecules that target the SF3b subunit of spliceosomal U2 snRNP. These compounds are attracting much attention as tools to manipulate splicing and potential anti-cancer drugs. We investigated the effects of these inhibitors on mRNA transport and stability in human cells. Upon splicing inhibition unspliced pre-mRNAs accumulated in the nucleus, particularly within enlarged nuclear speckles. Yet, a small fraction of the pre-mRNA molecules were exported to the cytoplasm...
March 16, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28300534/identification-of-a-small-molecule-inhibitor-that-stalls-splicing-at-an-early-step-of-spliceosome-activation
#19
Anzhalika Sidarovich, Cindy L Will, Maria M Anokhina, Javier Ceballos, Sonja Sievers, Dmitry E Agafonov, Timur Samatov, Penghui Bao, Berthold Kastner, Henning Urlaub, Herbert Waldmann, Reinhard Lührmann
Small molecule inhibitors of pre-mRNA splicing are important tools for identifying new spliceosome assembly intermediates, allowing a finer dissection of spliceosome dynamics and function. Here, we identified a small molecule that inhibits human pre-mRNA splicing at an intermediate stage during conversion of pre-catalytic spliceosomal B complexes into activated B(act) complexes. Characterization of the stalled complexes (designated B(028)) revealed that U4/U6 snRNP proteins are released during activation before the U6 Lsm and B-specific proteins, and before recruitment and/or stable incorporation of Prp19/CDC5L complex and other B(act) complex proteins...
March 16, 2017: ELife
https://www.readbyqxmd.com/read/28289156/u7-snrnp-is-recruited-to-histone-pre-mrna-in-a-flash-dependent-manner-by-two-separate-regions-of-the-stem-loop-binding-protein
#20
Aleksandra Skrajna, Xiao-Cui Yang, Katarzyna Bucholc, Jun Zhang, Traci M Hall, Michał Dadlez, William F Marzluff, Zbigniew Dominski
Cleavage of histone pre-mRNAs at the 3' end requires Stem-Loop Binding Protein (SLBP) and U7 snRNP that consists of U7 snRNA and a unique Sm ring containing two U7-specific proteins: Lsm10 and Lsm11. Lsm11 interacts with FLASH and together they bring a subset of polyadenylation factors to U7 snRNP, including the CPSF73 endonuclease that cleaves histone pre-mRNA. SLBP binds to a conserved stem-loop structure upstream of the cleavage site and acts by promoting an interaction between the U7 snRNP and a sequence element located downstream of the cleavage site...
March 13, 2017: RNA
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