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https://www.readbyqxmd.com/read/28935721/the-spliceosomal-proteins-ppih-and-prpf4-exhibit-bipartite-binding
#1
Caroline Rajiv, S RaElle Jackson, Simon Cocklin, Elan Z Eisenmesser, Tara Davis
Pre-mRNA splicing is a dynamic, multi-step process that is catalyzed by the RNA: protein complex called the spliceosome. The spliceosome contains a core set of RNAs and proteins that are conserved in all organisms that perform splicing. In higher organisms, PPIH directly interacts with the core protein PRPF4 and both integrate into the pre-catalytic spliceosome as part of the tri-snRNP sub-complex. As a first step to understand the protein interactions that dictate PPIH and PRPF4 function, we expressed and purified soluble forms of each protein and formed a complex between them...
September 21, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28935704/the-splicing-co-factor-barricade-tat-sf1-is-required-for-cell-cycle-and-lineage-progression-in-drosophila-neural-stem-cells
#2
Monika K Abramczuk, Thomas R Burkard, Vivien Rolland, Victoria Steinmann, Peter Duchek, Yanrui Jiang, Sebastian Wissel, Heinrich Reichert, Juergen A Knoblich
Stem cells need to balance self-renewal and differentiation for correct tissue development and homeostasis. Defects in this balance can lead to developmental defects or tumor formation. In recent years, mRNA splicing has emerged as one important mechanism regulating cell fate decisions. Here we address the role of the evolutionary conserved splicing co-factor Barricade (Barc)/Tat-SF1/CUS2 in Drosophila neural stem cell (neuroblast) lineage formation. We show that Barc is required for the generation of neurons during Drosophila brain development by ensuring correct neural progenitor proliferation and differentiation...
September 21, 2017: Development
https://www.readbyqxmd.com/read/28934473/the-conserved-au-dinucleotide-at-the-5-end-of-nascent-u1-snrna-is-optimized-for-the-interaction-with-nuclear-cap-binding-complex
#3
Chung-Shu Yeh, Shang-Lin Chang, Jui-Hui Chen, Hsuan-Kai Wang, Yue-Chang Chou, Chun-Hsiung Wang, Shih-Hsin Huang, Amy Larson, Jeffrey A Pleiss, Wei-Hau Chang, Tien-Hsien Chang
Splicing is initiated by a productive interaction between the pre-mRNA and the U1 snRNP, in which a short RNA duplex is established between the 5' splice site of a pre-mRNA and the 5' end of the U1 snRNA. A long-standing puzzle has been why the AU dincucleotide at the 5'-end of the U1 snRNA is highly conserved, despite the absence of an apparent role in the formation of the duplex. To explore this conundrum, we varied this AU dinucleotide into all possible permutations and analyzed the resulting molecular consequences...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28887445/usb1-controls-u6-snrnp-assembly-through-evolutionarily-divergent-cyclic-phosphodiesterase-activities
#4
Allison L Didychuk, Eric J Montemayor, Tucker J Carrocci, Andrew T DeLaitsch, Stefani E Lucarelli, William M Westler, David A Brow, Aaron A Hoskins, Samuel E Butcher
U6 small nuclear ribonucleoprotein (snRNP) biogenesis is essential for spliceosome assembly, but not well understood. Here, we report structures of the U6 RNA processing enzyme Usb1 from yeast and a substrate analog bound complex from humans. Unlike the human ortholog, we show that yeast Usb1 has cyclic phosphodiesterase activity that leaves a terminal 3' phosphate which prevents overprocessing. Usb1 processing of U6 RNA dramatically alters its affinity for cognate RNA-binding proteins. We reconstitute the post-transcriptional assembly of yeast U6 snRNP in vitro, which occurs through a complex series of handoffs involving 10 proteins (Lhp1, Prp24, Usb1 and Lsm2-8) and anti-cooperative interactions between Prp24 and Lhp1...
September 8, 2017: Nature Communications
https://www.readbyqxmd.com/read/28884683/characterisation-of-the-biflavonoid-hinokiflavone-as-a-pre-mrna-splicing-modulator-that-inhibits-senp
#5
Andrea Pawellek, Ursula Ryder, Triin Tammsalu, Lewis J King, Helmi Kreinin, Tony Ly, Ronald T Hay, Richard Hartley, Angus I Lamond
We have identified the plant biflavonoid hinokiflavone as an inhibitor of splicing in vitro and modulator of alternative splicing in cells. Chemical synthesis confirms hinokiflavone is the active molecule. Hinokiflavone inhibits splicing in vitro by blocking spliceosome assembly, leading to accumulation of the A complex. Cells treated with hinokiflavone show altered subnuclear organization specifically of splicing factors required for A complex formation, which relocalize together with SUMO1 and SUMO2 into enlarged nuclear speckles...
September 8, 2017: ELife
https://www.readbyqxmd.com/read/28879433/cbp-mediated-smn-acetylation-modulates-cajal-body-biogenesis-and-the-cytoplasmic-targeting-of-smn
#6
Vanesa Lafarga, Olga Tapia, Sahil Sharma, Rocio Bengoechea, Georg Stoecklin, Miguel Lafarga, Maria T Berciano
The survival of motor neuron (SMN) protein plays an essential role in the biogenesis of spliceosomal snRNPs and the molecular assembly of Cajal bodies (CBs). Deletion of or mutations in the SMN1 gene cause spinal muscular atrophy (SMA) with degeneration and loss of motor neurons. Reduced SMN levels in SMA lead to deficient snRNP biogenesis with consequent splicing pathology. Here, we demonstrate that SMN is a novel and specific target of the acetyltransferase CBP (CREB-binding protein). Furthermore, we identify lysine (K) 119 as the main acetylation site in SMN...
September 6, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28878233/a-chalcone-derivative-reactivates-latent-hiv-1-transcription-through-activating-p-tefb-and-promoting-tat-sec-interaction-on-viral-promoter
#7
Jun Wu, Ming-Tao Ao, Rui Shao, Hui-Ru Wang, Diao Yu, Mei-Juan Fang, Xiang Gao, Zhen Wu, Qiang Zhou, Yu-Hua Xue
The principal barrier to the eradication of HIV/AIDS is the existence of latent viral reservoirs. One strategy to overcome this barrier is to use latency-reversing agents (LRAs) to reactivate the latent proviruses, which can then be eliminated by effective anti-retroviral therapy. Although a number of LRAs have been found to reactivate latent HIV, they have not been used clinically due to high toxicity and poor efficacy. In this study, we report the identification of a chalcone analogue called Amt-87 that can significantly reactivate the transcription of latent HIV provirses and act synergistically with known LRAs such as prostratin and JQ1 to reverse latency...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28878028/basal-a-triple-negative-breast-cancer-cells-selectively-rely-on-rna-splicing-for-survival
#8
Stefanie Chan, Praveen Sridhar, Rory Kirchner, Ying Jie Lock, Zach Herbert, Silvia Buonamici, Peter Smith, Judy Lieberman, Fabio Petrocca
Prognosis of triple-negative breast cancer (TNBC) remains poor. To identify shared and selective vulnerabilities of basal-like TNBC, the most common TNBC subtype, a directed siRNA lethality screen was performed in 7 human breast cancer cell lines, focusing on 154 previously identified dependency genes of one TNBC line. Thirty common dependency genes were identified, including multiple proteasome and RNA splicing genes, especially those associated with the U4/U6.U5 tri-snRNP complex (e.g., PRPF8, PRPF38A). PRPF8 or PRPF38A knockdown or the splicing modulator E7107 led to widespread intronic retention and altered splicing of transcripts involved in multiple basal-like TNBC dependencies, including protein homeostasis, mitosis and apoptosis...
September 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28878014/identification-of-a-35s-u4-u6-u5-tri-snrnp-complex-intermediate-in-spliceosome-assembly
#9
Zhe Chen, Bin Gui, Yu Zhang, Guojia Xie, Wanjin Li, Shumeng Liu, Bosen Xu, Chongyang Wu, Lin He, Jianguo Yang, Xia Yi, Xiaohan Yang, Luyang Sun, Jing Liang, Yongfeng Shang
The de novo assembly and post-splicing reassembly of the U4/U6.U5 tri-snRNP remain to be investigated. We report here that ZIP, a protein containing a CCCH type of zinc finger and a G-patch domain as we characterized previously, regulates pre-mRNA splicing in a RNA binding-independent manner. We found that ZIP is physically associated with the U4/U6.U5 tri-snRNP. Remarkably, ZIP-containing tri-snRNP has a sedimentation coefficient ~35S, a tri-snRNP that has not been described before. We showed that the 35S tri-snRNP contains hPrp24, indicative of a state when the U4/U6 di-snRNP is just integrating with the U5 snRNP...
September 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28876172/variant-snrnps-new-players-within-the-spliceosome-system
#10
Pilar Vazquez-Arango, Dawn O'Reilly
Much evidence is now accumulating that, in addition to their general role in splicing, the components of the core splicing machinery have extensive regulatory potential. In particular, recent evidence has demonstrated that de-regulation of these factors cause the highest extent of alternative splicing changes compared to de-regulation of the classical splicing regulators. This lack of a general inhibition of splicing resonates the differential splicing effects observed in different disease pathologies associated with specific mutations targeting core spliceosomal components...
September 6, 2017: RNA Biology
https://www.readbyqxmd.com/read/28874828/srsf1-suppresses-selection-of-intron-distal-5-splice-site-of-dok7-intron-4-to-generate-functional-full-length-dok-7-protein
#11
Khalid Bin Ahsan, Akio Masuda, Mohammad Alinoor Rahman, Jun-Ichi Takeda, Mohammad Nazim, Bisei Ohkawara, Mikako Ito, Kinji Ohno
Dok-7 is a non-catalytic adaptor protein that facilitates agrin-induced clustering of acetylcholine receptors (AChR) at the neuromuscular junction. Alternative selection of 5' splice sites (SSs) of DOK7 intron 4 generates canonical and frame-shifted transcripts. We found that the canonical full-length Dok-7 enhanced AChR clustering, whereas the truncated Dok-7 did not. We identified a splicing cis-element close to the 3' end of exon 4 by block-scanning mutagenesis. RNA affinity purification and mass spectrometry revealed that SRSF1 binds to the cis-element...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28867047/birth-and-death-of-histone-mrnas
#12
REVIEW
William F Marzluff, Kaitlin P Koreski
In metazoans, histone mRNAs are not polyadenylated but end in a conserved stem-loop. Stem-loop binding protein (SLBP) binds to the stem-loop and is required for all steps in histone mRNA metabolism. The genes for the five histone proteins are linked. A histone locus body (HLB) forms at each histone gene locus. It contains factors essential for transcription and processing of histone mRNAs, and couples transcription and processing. The active form of U7 snRNP contains the HLB component FLASH (FLICE-associated huge protein), the histone cleavage complex (HCC), and a subset of polyadenylation factors including the endonuclease CPSF73...
August 31, 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/28838205/a-new-role-for-fbp21-as-regulator-of-brr2-helicase-activity
#13
Lisa M Henning, Karine F Santos, Jana Sticht, Stefanie Jehle, Chung-Tien Lee, Malte Wittwer, Henning Urlaub, Ulrich Stelzl, Markus C Wahl, Christian Freund
Splicing of eukaryotic pre-mRNA is carried out by the spliceosome, which assembles stepwise on each splicing substrate. This requires the concerted action of snRNPs and non-snRNP accessory proteins, the functions of which are often not well understood. Of special interest are B complex factors that enter the spliceosome prior to catalytic activation and may alter splicing kinetics and splice site selection. One of these proteins is FBP21, for which we identified several spliceosomal binding partners in a yeast-two-hybrid screen, among them the RNA helicase Brr2...
July 27, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28837687/the-spliceosome-associated-protein-mfap1-binds-to-vcp-in-drosophila
#14
Sandra Rode, Henrike Ohm, Jaqueline Zipfel, Sebastian Rumpf
Posttranscriptional regulation of gene expression contributes to many developmental transitions. Previously, we found that the AAA chaperone Valosin-Containing Protein (VCP) regulates ecdysone-dependent dendrite pruning of Drosophila class IV dendritic arborization (c4da) neurons via an effect on RNA metabolism. In a search for RNA binding proteins associated with VCP, we identified the spliceosome-associated protein Mfap1, a component of the tri-snRNP complex. Mfap1 is a nucleolar protein in neurons and its levels are regulated by VCP...
2017: PloS One
https://www.readbyqxmd.com/read/28829039/dynamics-and-consequences-of-spliceosome-e-complex-formation
#15
Joshua Donald Larson, Aaron A Hoskins
The spliceosome must identify the correct splice sites (SS) and branchsite (BS) used during splicing. E complex is the earliest spliceosome precursor in which the 5' SS and BS are defined. Definition occurs by U1 small nuclear ribonucleoprotein (snRNP) binding the 5' SS and recognition of the BS by the E complex protein (ECP) branchpoint bridging protein (BBP). We have used single molecule fluorescence to study Saccharomyces cerevisiae U1 and BBP interactions with RNAs. E complex is dynamic and permits frequent redefinition of the 5' SS and BS...
August 22, 2017: ELife
https://www.readbyqxmd.com/read/28781166/cryo-em-structure-of-a-pre-catalytic-human-spliceosome-primed-for-activation
#16
Karl Bertram, Dmitry E Agafonov, Olexandr Dybkov, David Haselbach, Majety N Leelaram, Cindy L Will, Henning Urlaub, Berthold Kastner, Reinhard Lührmann, Holger Stark
Little is known about the spliceosome's structure before its extensive remodeling into a catalytically active complex. Here, we report a 3D cryo-EM structure of a pre-catalytic human spliceosomal B complex. The U2 snRNP-containing head domain is connected to the B complex main body via three main bridges. U4/U6.U5 tri-snRNP proteins, which are located in the main body, undergo significant rearrangements during tri-snRNP integration into the B complex. These include formation of a partially closed Prp8 conformation that creates, together with Dim1, a 5' splice site (ss) binding pocket, displacement of Sad1, and rearrangement of Brr2 such that it contacts its U4/U6 substrate and is poised for the subsequent spliceosome activation step...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28768202/dual-rna-processing-roles-of-pat1b-via-cytoplasmic-lsm1-7-and-nuclear-lsm2-8-complexes
#17
Caroline Vindry, Aline Marnef, Helen Broomhead, Laure Twyffels, Sevim Ozgur, Georg Stoecklin, Miriam Llorian, Christopher W Smith, Juan Mata, Dominique Weil, Nancy Standart
Pat1 RNA-binding proteins, enriched in processing bodies (P bodies), are key players in cytoplasmic 5' to 3' mRNA decay, activating decapping of mRNA in complex with the Lsm1-7 heptamer. Using co-immunoprecipitation and immunofluorescence approaches coupled with RNAi, we provide evidence for a nuclear complex of Pat1b with the Lsm2-8 heptamer, which binds to the spliceosomal U6 small nuclear RNA (snRNA). Furthermore, we establish the set of interactions connecting Pat1b/Lsm2-8/U6 snRNA/SART3 and additional U4/U6...
August 1, 2017: Cell Reports
https://www.readbyqxmd.com/read/28751196/discovery-of-spiro-indole-3-2-pyrrolidin-2-1h-one-based-inhibitors-targeting-brr2-a-core-component-of-the-u5-snrnp
#18
Masahiro Ito, Misa Iwatani, Takeshi Yamamoto, Toshio Tanaka, Tomohiro Kawamoto, Daisuke Morishita, Atsushi Nakanishi, Hironobu Maezaki
Bad response to refrigeration 2 (Brr2) is a member of the Ski2-like RNA helicases, and an essential component of the U5 small nuclear ribonucleoprotein (snRNP). A particularly important role of Brr2 is the ATP-dependent unwinding of the U4/U6 RNA duplex, which is a critical step in spliceosomal activation. Despite its biological importance, selective inhibitor for Brr2 had not been reported until our recent report. Here, we describe novel and structurally distinct spiro[indole-3,2'-pyrrolidin]-2(1H)-one based Brr2 inhibitors with superior activity to the previously reported 4,6-dihydropyrido[4,3-d]pyrimidine-2,7(1H,3H)-dione series...
July 13, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28701519/nineteen-complex-related-factor-prp45-is-required-for-the-early-stages-of-cotranscriptional-spliceosome-assembly
#19
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
#20
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...
September 6, 2017: Nucleic Acids Research
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