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https://www.readbyqxmd.com/read/28701519/nineteen-complex-related-factor-prp45-is-required-for-the-early-stages-of-cotranscriptional-spliceosome-assembly
#1
Martina Hálová, Ondřej Gahura, Martin Převorovský, Zdeněk Cit, Marian Novotný, Anna Valentová, Kateřina Abrhámová, František Půta, Petr Folk
Splicing in S. cerevisiae has been shown to proceed cotranscriptionally, but the nature of the coupling remains a subject of debate. Here, we examine the effect of nineteen complex-related splicing factor Prp45 (a homolog of SNW1/SKIP) on cotranscriptional splicing. RNA-sequencing and RT-qPCR showed elevated pre-mRNA levels but only limited reduction of spliced mRNAs in cells expressing C-terminally truncated Prp45, Prp45(1-169). Assays with a series of reporters containing the AMA1 intron with regulatable splicing confirmed decreased splicing efficiency and showed the leakage of unspliced RNAs in prp45(1-169) cells...
July 12, 2017: RNA
https://www.readbyqxmd.com/read/28666385/human-ribosomal-protein-es1-is-engaged-in-cellular-events-related-to-processing-and-functioning-of-u11-snrna
#2
Alexander V Gopanenko, Alexey A Malygin, Alexey E Tupikin, Pavel P Laktionov, Marsel R Kabilov, Galina G Karpova
Ribosomal proteins are involved in many cellular processes through interactions with various RNAs. Here, applying the photoactivatable-ribonucleoside-enhanced cross-linking and immunoprecipitation approach to HEK293 cells overproducing ribosomal protein (rp) eS1, we determined the products of RNU5A-1 and RNU11 genes encoding U5 and U11 snRNAs as the RNA partners of ribosome-unbound rp eS1. U11 pre-snRNA-associated rp eS1 was revealed in the cytoplasm and nucleus where rp eS1-bound U11/U12 di-snRNP was also found...
June 28, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28648680/reversibly-constraining-spliceosome-substrate-complexes-by-engineering-disulfide-crosslinks
#3
Patrick McCarthy, Erin Garside, Yonatan Meschede-Krasa, Andrew MacMillan, Daniel Pomeranz Krummel
The spliceosome is a highly dynamic mega-Dalton enzyme, formed in part by assembly of U snRNPs onto its pre-mRNA substrate transcripts. Early steps in spliceosome assembly are challenging to study biochemically and structurally due to compositional and conformational dynamics. We detail an approach to covalently and reversibly constrain or trap non-covalent pre-mRNA/protein spliceosome complexes. This approach involves engineering a single disulfide bond between a thiol-bearing cysteine sidechain and a proximal backbone phosphate of the pre-mRNA, site-specifically modified with an N-thioalkyl moiety...
June 22, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28642865/spinal-muscular-atrophy-from-defective-chaperoning-of-snrnp-assembly-to-neuromuscular-dysfunction
#4
REVIEW
Maia Lanfranco, Neville Vassallo, Ruben J Cauchi
Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN) protein. SMN is part of a multiprotein complex that also includes Gemins 2-8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5) complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs) to generate small nuclear ribonucleoproteins (snRNPs), which are the operating components of the spliceosome...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28614712/evidence-that-c9orf72-dipeptide-repeat-proteins-associate-with-u2-snrnp-to-cause-mis-splicing-in-als-ftd-patients
#5
Shanye Yin, Rodrigo Lopez-Gonzalez, Ryan C Kunz, Jaya Gangopadhyay, Carl Borufka, Steven P Gygi, Fen-Biao Gao, Robin Reed
Hexanucleotide repeat expansion in the C9ORF72 gene results in production of dipeptide repeat (DPR) proteins that may disrupt pre-mRNA splicing in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. At present, the mechanisms underlying this mis-splicing are not understood. Here, we show that addition of proline-arginine (PR) and glycine-arginine (GR) toxic DPR peptides to nuclear extracts blocks spliceosome assembly and splicing, but not other types of RNA processing. Proteomic and biochemical analyses identified the U2 small nuclear ribonucleoprotein particle (snRNP) as a major interactor of PR and GR peptides...
June 13, 2017: Cell Reports
https://www.readbyqxmd.com/read/28596291/ddx54-regulates-transcriptome-dynamics-during-dna-damage-response
#6
Miha Milek, Koshi Imami, Neelanjan Mukherjee, Francesca De Bortoli, Ulrike Zinnall, Orsalia Hazapis, Christian Trahan, Marlene Oeffinger, Florian Heyd, Uwe Ohler, Matthias Selbach, Markus Landthaler
The cellular response to genotoxic stress is mediated by a well-characterized network of DNA surveillance pathways. The contribution of posttranscriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. Here, we systematically identified RNA-binding proteins differentially interacting with polyadenylated transcripts upon exposure of human breast carcinoma cells to ionizing radiation (IR). Interestingly, more than 260 proteins including many nucleolar proteins showed increased binding to poly(A) RNA in IR-exposed cells...
June 8, 2017: Genome Research
https://www.readbyqxmd.com/read/28592461/rbm24-promotes-u1-snrnp-recognition-of-the-mutated-5-splice-site-in-the-ikbkap-gene-of-familial-dysautonomia
#7
Kenji Ohe, Mayumi Yoshida, Akiko Nakano-Kobayashi, Motoyasu Hosokawa, Yukiya Sako, Maki Sakuma, Yukiko Okuno, Tomomi Usui, Kensuke Ninomiya, Takayuki Nojima, Naoyuki Kataoka, Masatoshi Hagiwara
The 5' splice site mutation (IVS20+6T>C) of the inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) gene in familial dysautonomia (FD) is at the sixth intronic nucleotide of the 5' splice site. It is known to weaken U1 snRNP recognition and result in aberrantly spliced mRNA product in neuronal tissue, but normally spliced mRNA in other tissues. Aberrantly spliced IKBKAP mRNA abrogates IKK complex-associated protein (IKAP)/elongator protein 1 (ELP1) expression and results in a defect of neuronal cell development in FD...
June 7, 2017: RNA
https://www.readbyqxmd.com/read/28589955/crystal-structures-of-u6-snrna-specific-terminal-uridylyltransferase
#8
Seisuke Yamashita, Yuko Takagi, Takashi Nagaike, Kozo Tomita
The terminal uridylyltransferase, TUT1, builds or repairs the 3'-oligo-uridylylated tail of U6 snRNA. The 3'-oligo-uridylylated tail is the Lsm-binding site for U4/U6 di-snRNP formation and U6 snRNA recycling for pre-mRNA splicing. Here, we report crystallographic and biochemical analyses of human TUT1, which revealed the mechanisms for the specific uridylylation of the 3'-end of U6 snRNA by TUT1. The O2 and O4 atoms of the UTP base form hydrogen bonds with the conserved His and Asn in the catalytic pocket, respectively, and TUT1 preferentially incorporates UMP onto the 3'-end of RNAs...
June 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/28561026/r2tp-prefoldin-like-component-ruvbl1-ruvbl2-directly-interacts-with-znhit2-to-regulate-assembly-of-u5-small-nuclear-ribonucleoprotein
#9
Philippe Cloutier, Christian Poitras, Mathieu Durand, Omid Hekmat, Émilie Fiola-Masson, Annie Bouchard, Denis Faubert, Benoit Chabot, Benoit Coulombe
The R2TP/Prefoldin-like (R2TP/PFDL) complex has emerged as a cochaperone complex involved in the assembly of a number of critical protein complexes including snoRNPs, nuclear RNA polymerases and PIKK-containing complexes. Here we report on the use of multiple target affinity purification coupled to mass spectrometry to identify two additional complexes that interact with R2TP/PFDL: the TSC1-TSC2 complex and the U5 small nuclear ribonucleoprotein (snRNP). The interaction between R2TP/PFDL and the U5 snRNP is mostly mediated by the previously uncharacterized factor ZNHIT2...
May 31, 2017: Nature Communications
https://www.readbyqxmd.com/read/28549066/alternative-exon-definition-events-control-the-choice-between-nuclear-retention-and-cytoplasmic-export-of-u11-u12-65k-mrna
#10
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 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28530653/structure-of-a-pre-catalytic-spliceosome
#11
Clemens Plaschka, Pei-Chun Lin, Kiyoshi Nagai
Intron removal requires assembly of the spliceosome on precursor mRNA (pre-mRNA) and extensive remodelling to form the spliceosome's catalytic centre. Here we report the cryo-electron microscopy structure of the yeast Saccharomyces cerevisiae pre-catalytic B complex spliceosome at near-atomic resolution. The mobile U2 small nuclear ribonucleoprotein particle (snRNP) associates with U4/U6.U5 tri-snRNP through the 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...
June 29, 2017: Nature
https://www.readbyqxmd.com/read/28515487/functional-interaction-between-fus-and-smn-underlies-sma-like-splicing-changes-in-wild-type-hfus-mice
#12
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
#13
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...
June 5, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28502770/an-atomic-structure-of-the-human-spliceosome
#14
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
#15
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 might 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...
July 5, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28482101/environment-dependent-regulation-of-spliceosome-activity-by-the-lsm2-8-complex-in-arabidopsis
#16
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
#17
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. Noncoding exons 2/2b contain the Vif start codon between their alternatively used splice donors 2 and 2b (D2 and D2b). For 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...
July 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28446598/the-histone-variant-h2a-z-promotes-efficient-cotranscriptional-splicing-in-s-cerevisiae
#18
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
#19
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
#20
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
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