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https://www.readbyqxmd.com/read/28103691/sudemycin-k-a-synthetic-antitumor-splicing-inhibitor-variant-with-improved-activity-and-versatile-chemistry
#1
Kamil Makowski, Luisa Vigevani, Fernando Albericio, Juan Valcárcel, Mercedes Álvarez
Important links exist between the process of pre-mRNA splicing and cancer, as illustrated by the frequent mutation of splicing factors in tumors and the emergence of various families of antitumor drugs that target components of the splicing machinery, notably SF3B1, a protein subunit of spliceosomal U2 small nuclear ribonucleoprotein particle (snRNP). Sudemycins are synthetic compounds that harbor a pharmacophore common to various classes of splicing inhibitors. Here, we describe the synthesis and functional characterization of novel sudemycin analogues that functionally probe key chemical groups within this pharmacophore...
January 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28102760/phf13-a-new-player-involved-in-rna-polymerase-ii-transcriptional-regulation-and-co-transcriptional-splicing
#2
Alisa Fuchs, Marcos Torroba, Sarah Kinkley
We recently identified PHF13 as an H3K4me2/3 chromatin reader and transcriptional co-regulator. We found that PHF13 interacts with RNAPIIS5P and PRC2 stabilizing their association with active and bivalent promoters. Furthermore, mass spectrometry analysis identified ∼50 spliceosomal proteins in PHF13's interactome. Here we will discuss the potential role of PHF13 in RNAPII pausing and co-transcriptional splicing.
January 19, 2017: Transcription
https://www.readbyqxmd.com/read/28095062/microrna-196a-as-a-potential-diagnostic-biomarker-for-esophageal-squamous-cell-carcinoma
#3
Mona Fendereski, Mohammad Farid Zia, Mohammad Shafiee, Forousan Safari, Mohammad Hosien Saneie, Manoochehr Tavassoli
We observed significant up-regulation of miR-196a in esophageal squamous cell carcinoma (ESCC) as compared with their adjacent normal tissue (p = .002). Receiver operating characteristics curve analysis confirmed the suitability of miR-196a as a potential tumor marker for diagnosis of ESCC. Furthermore, analysis of miR-196a levels in saliva samples determined an average of 27-fold up-regulations in ESCC patients compared with healthy group. Our results suggest that salivary miR-196a may be a suitable noninvasive biomarker for diagnosis of ESCC...
January 17, 2017: Cancer Investigation
https://www.readbyqxmd.com/read/28092684/biallelic-mutations-in-the-3-exonuclease-toe1-cause-pontocerebellar-hypoplasia-and-uncover-a-role-in-snrna-processing
#4
Rea M Lardelli, Ashleigh E Schaffer, Veerle R C Eggens, Maha S Zaki, Stephanie Grainger, Shashank Sathe, Eric L Van Nostrand, Zinayida Schlachetzki, Basak Rosti, Naiara Akizu, Eric Scott, Jennifer L Silhavy, Laura Dean Heckman, Rasim Ozgur Rosti, Esra Dikoglu, Anne Gregor, Alicia Guemez-Gamboa, Damir Musaev, Rohit Mande, Ari Widjaja, Tim L Shaw, Sebastian Markmiller, Isaac Marin-Valencia, Justin H Davies, Linda de Meirleir, Hulya Kayserili, Umut Altunoglu, Mary Louise Freckmann, Linda Warwick, David Chitayat, Susan Blaser, Ahmet Okay Çağlayan, Kaya Bilguvar, Huseyin Per, Christina Fagerberg, Henrik T Christesen, Maria Kibaek, Kimberly A Aldinger, David Manchester, Naomichi Matsumoto, Kazuhiro Muramatsu, Hirotomo Saitsu, Masaaki Shiina, Kazuhiro Ogata, Nicola Foulds, William B Dobyns, Neil C Chi, David Traver, Luigina Spaccini, Stefania Maria Bova, Stacey B Gabriel, Murat Gunel, Enza Maria Valente, Marie-Cecile Nassogne, Eric J Bennett, Gene W Yeo, Frank Baas, Jens Lykke-Andersen, Joseph G Gleeson
Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg(2+)-dependent 3'-end RNases with substrate specificity that is mostly unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase...
January 16, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28092261/structural-insights-into-the-mechanism-of-the-deah-box-rna-helicase-prp43
#5
Marcel J Tauchert, Jean-Baptiste Fourmann, Reinhard Lührmann, Ralf Ficner
The DEAH-box helicase Prp43 is a key player in pre-mRNA splicing as well as the maturation of rRNAs. The exact modus operandi of Prp43 and of all other spliceosomal DEAH-box RNA helicases is still elusive. Here, we report crystal structures of Prp43 complexes in different functional states and the analysis of structure-based mutants providing insights into the unwinding and loading mechanism of RNAs. The Prp43•ATP-analog•RNA complex shows the localization of the RNA inside a tunnel formed by the two RecA-like and C-terminal domains...
January 16, 2017: ELife
https://www.readbyqxmd.com/read/28088760/usp15-regulates-dynamic-protein-protein-interactions-of-the-spliceosome-through-deubiquitination-of-prp31
#6
Tanuza Das, Joon Kyu Park, Jinyoung Park, Eunji Kim, Michael Rape, Eunice EunKyeong Kim, Eun Joo Song
Post-translational modifications contribute to the spliceosome dynamics by facilitating the physical rearrangements of the spliceosome. Here, we report USP15, a deubiquitinating enzyme, as a regulator of protein-protein interactions for the spliceosome dynamics. We show that PRP31, a component of U4 snRNP, is modified with K63-linked ubiquitin chains by the PRP19 complex and deubiquitinated by USP15 and its substrate targeting factor SART3. USP15(SART3) makes a complex with USP4 and this ternary complex serves as a platform to deubiquitinate PRP31 and PRP3...
January 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28087715/sf3b1-hsh155-heat-motif-mutations-affect-interaction-with-the-spliceosomal-atpase-prp5-resulting-in-altered-branch-site-selectivity-in-pre-mrna-splicing
#7
Qing Tang, Susana Rodriguez-Santiago, Jing Wang, Jia Pu, Andrea Yuste, Varun Gupta, Alberto Moldón, Yong-Zhen Xu, Charles C Query
Mutations in the U2 snRNP component SF3B1 are prominent in myelodysplastic syndromes (MDSs) and other cancers and have been shown recently to alter branch site (BS) or 3' splice site selection in splicing. However, the molecular mechanism of altered splicing is not known. We show here that hsh155 mutant alleles in Saccharomyces cerevisiae, counterparts of SF3B1 mutations frequently found in cancers, specifically change splicing of suboptimal BS pre-mRNA substrates. We found that Hsh155p interacts directly with Prp5p, the first ATPase that acts during spliceosome assembly, and localized the interacting regions to HEAT (Huntingtin, EF3, PP2A, and TOR1) motifs in SF3B1 associated with disease mutations...
December 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/28087625/faithful-mrna-splicing-depends-on-the-prp19-complex-subunit-faint-sausage-and-is-required-for-tracheal-branching-morphogenesis-in-drosophila
#8
Julia Sauerwald, Charlotte Soneson, Mark D Robinson, Stefan Luschnig
Morphogenesis requires the dynamic regulation of gene expression, including transcription, mRNA maturation and translation. Dysfunction of the general mRNA splicing machinery can cause surprisingly specific cellular phenotypes, but the basis for these effects is not clear. Here we show that the Drosophila faint sausage (fas) locus, implicated in epithelial morphogenesis and previously reported to encode a secreted immunoglobulin domain protein, in fact encodes a subunit of the spliceosome-activating Prp19 complex, which is essential for efficient pre-mRNA splicing...
January 13, 2017: Development
https://www.readbyqxmd.com/read/28078605/transcriptional-regulatory-network-analysis-for-gastric-cancer-based-on-mrna-microarray
#9
Yan Wang
We aimed to screen the differential expressed genes (DEGs) and transcriptional factors (TFs) related to gastric cancer. GSE19826 microarray data downloaded from Gene Expression Omnibus was used to identify the differentially expressed genes (DEGs) and PPI network of DEGs were constructed by the Retrieval of Interacting Genes database. Pathway enrichment analysis of DEGs were performed by Gene Set Enrichment Analysis. Then, the transcriptional regulatory network was constructed based on TRANSFAC database. Finally, regulatory impact factor (RIF) of TF was calculated...
January 11, 2017: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/28076437/mutations-in-splicing-factor-genes-are-a-major-cause-of-autosomal-dominant-retinitis-pigmentosa-in-belgian-families
#10
Caroline Van Cauwenbergh, Frauke Coppieters, Dimitri Roels, Sarah De Jaegere, Helena Flipts, Julie De Zaeytijd, Sophie Walraedt, Charlotte Claes, Erik Fransen, Guy Van Camp, Fanny Depasse, Ingele Casteels, Thomy de Ravel, Bart P Leroy, Elfride De Baere
PURPOSE: Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition. METHODS: Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization)...
2017: PloS One
https://www.readbyqxmd.com/read/28076346/cryo-em-structure-of-a-human-spliceosome-activated-for-step-2-of-splicing
#11
Karl Bertram, Dmitry E Agafonov, Wen-Ti Liu, Olexandr Dybkov, Cindy L Will, Klaus Hartmuth, Henning Urlaub, Berthold Kastner, Holger Stark, Reinhard Lu Hrmann
Spliceosome rearrangements facilitated by RNA helicase Prp16 before catalytic step 2 of splicing are poorly understood. Here we report a 3D cryo-electron microscopy structure of the human spliceosomal C complex stalled directly after Prp16 action (C*). The architecture of the catalytic U2-U6 RNP core of the human C* spliceosome is highly similar to that of the yeast pre-Prp16 C complex. However, in C* the branched intron region is separated (by ~20 Å) from the catalytic centre, and its position close to the U6 snRNA ACAGA box is stabilised by interactions with the Prp8 RNase H-like and Prp17 WD40 domains...
January 11, 2017: Nature
https://www.readbyqxmd.com/read/28076345/structure-of-a-spliceosome-remodelled-for-exon-ligation
#12
Sebastian M Fica, Chris Oubridge, Wojciech P Galej, Max E Wilkinson, Xiao-Chen Bai, Andrew J Newman, Kiyoshi Nagai
The spliceosome excises introns from pre-mRNAs in two sequential trans-esterifications - branching and exon ligation(1) - catalysed at a single catalytic metal site in U6 snRNA(2,3). The recent structures of the spliceosomal C complex(4,5) with the cleaved 5'-exon and lariat-3'-exon bound to the catalytic centre revealed that branching-specific factors such as Cwc25 lock the branch helix into position for nucleophilic attack of the branch adenosine at the 5'-splice site. Furthermore, the ATPase Prp16 is positioned to bind and translocate the intron downstream of the branch point to destabilize branching-specific factors and release the branch helix from the active site(4)...
January 11, 2017: Nature
https://www.readbyqxmd.com/read/28067246/mutant-u2af1-expressing-cells-are-sensitive-to-pharmacological-modulation-of-the-spliceosome
#13
Cara Lunn Shirai, Brian S White, Manorama Tripathi, Roberto Tapia, James N Ley, Matthew Ndonwi, Sanghyun Kim, Jin Shao, Alexa Carver, Borja Saez, Robert S Fulton, Catrina Fronick, Michelle O'Laughlin, Chandraiah Lagisetti, Thomas R Webb, Timothy A Graubert, Matthew J Walter
Somatic mutations in spliceosome genes are detectable in ∼50% of patients with myelodysplastic syndromes (MDS). We hypothesize that cells harbouring spliceosome gene mutations have increased sensitivity to pharmacological perturbation of the spliceosome. We focus on mutant U2AF1 and utilize sudemycin compounds that modulate pre-mRNA splicing. We find that haematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, have an increased sensitivity to in vitro sudemycin treatment relative to controls...
January 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28062854/sf3b1-mutations-associated-with-myelodysplastic-syndromes-alter-the-fidelity-of-branchsite-selection-in-yeast
#14
Tucker J Carrocci, Douglas M Zoerner, Joshua C Paulson, Aaron A Hoskins
RNA and protein components of the spliceosome work together to identify the 5' splice site, the 3' splice site, and the branchsite (BS) of nascent pre-mRNA. SF3b1 plays a key role in recruiting the U2 snRNP to the BS. Mutations in human SF3b1 have been linked to many diseases such as myelodysplasia (MDS) and cancer. We have used SF3b1 mutations associated with MDS to interrogate the role of the yeast ortholog, Hsh155, in BS selection and splicing. These alleles change how the spliceosome recognizes the BS and alter splicing when nonconsensus nucleotides are present at the -2, -1 and +1 positions relative to the branchpoint adenosine...
January 6, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28062851/human-cactin-interacts-with-dhx8-and-srrm2-to-assure-efficient-pre-mrna-splicing-and-sister-chromatid-cohesion
#15
Isabella M Y Zanini, Charlotte Soneson, Luca E Lorenzi, Claus M Azzalin
Cactins constitute a family of eukaryotic proteins broadly conserved from yeast to human and required for fundamental processes such as cell proliferation, genome stability maintenance, organismal development and immune response. Cactin proteins have been found to associate with the spliceosome in several model organisms, nevertheless their molecular functions await elucidation. Here we show that depletion of human Cactin (hCactin) leads to premature sister chromatid separation, genome instability and cell proliferation arrest...
January 6, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28058097/genetics-and-epigenetics-of-myelodysplastic-syndromes-and-response-to-drug-therapy-new-insights
#16
REVIEW
Saeid Shahrabi, Abbas Khosravi, Mohammad Shahjahani, Fakher Rahim, Najmaldin Saki
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms ocurring mostly in the elderly. The clinical outcome of MDS patients is still poor despite progress in treatment approaches. About 90% of patients harbor at least one somatic mutation. This review aimed to assess the potential of molecular abnormalities in understanding pathogenesis, prognosis, diagnosis and in guiding choice of proper therapy in MDS patients. Papers related to this topic from 2000 to 2016 in PubMed and Scopus databases were searched and studied...
October 10, 2016: Oncology Reviews
https://www.readbyqxmd.com/read/28057857/a-central-role-of-cwc25-in-spliceosome-dynamics-during-catalytic-phase-of-pre-mrna-splicing
#17
Chi-Kang Tseng, Che-Sheng Chung, Hsin-Chou Chen, Soo-Chen Cheng
Splicing of precursor mRNA occurs via two consecutive steps of transesterification reaction; both require ATP and several proteins. Despite the energy requirement in the catalytic phase, incubation of the purified spliceosome under proper ionic conditions can elicit competitive reversible transesterification, debranching and spliced-exon-reopening reactions without necessity for ATP or other factors, suggesting that small changes in the conformational state of the spliceosome can lead to disparate chemical consequences for the substrate...
January 5, 2017: RNA
https://www.readbyqxmd.com/read/28046103/transcriptome-profiling-identifies-ribosome-biogenesis-as-a-target-of-alcohol-teratogenicity-and-vulnerability-during-early-embryogenesis
#18
Mark E Berres, Ana Garic, George R Flentke, Susan M Smith
Fetal alcohol spectrum disorder (FASD) is a leading cause of neurodevelopmental disability. Individuals with FASD may exhibit a characteristic facial appearance that has diagnostic utility. The mechanism by which alcohol disrupts craniofacial development is incompletely understood, as are the genetic factors that can modify individual alcohol vulnerability. Using an established avian model, we characterized the cranial transcriptome in response to alcohol to inform the mechanism underlying these cells' vulnerability...
2017: PloS One
https://www.readbyqxmd.com/read/28045452/design-and-experimental-evolution-of-trans-splicing-group-i-intron-ribozymes
#19
REVIEW
Ulrich F Müller
Group I intron ribozymes occur naturally as cis-splicing ribozymes, in the form of introns that do not require the spliceosome for their removal. Instead, they catalyze two consecutive trans-phosphorylation reactions to remove themselves from a primary transcript, and join the two flanking exons. Designed, trans-splicing variants of these ribozymes replace the 3'-portion of a substrate with the ribozyme's 3'-exon, replace the 5'-portion with the ribozyme's 5'-exon, or insert/remove an internal sequence of the substrate...
January 2, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28045380/structure-and-conformational-plasticity-of-the-u6-small-nuclear-ribonucleoprotein-core
#20
Eric J Montemayor, Allison L Didychuk, Honghong Liao, Panzhou Hu, David A Brow, Samuel E Butcher
U6 small nuclear RNA (snRNA) is a key component of the active site of the spliceosome, a large ribonucleoprotein complex that catalyzes the splicing of precursor messenger RNA. Prior to its incorporation into the spliceosome, U6 is bound by the protein Prp24, which facilitates unwinding of the U6 internal stem-loop (ISL) so that it can pair with U4 snRNA. A previously reported crystal structure of the `core' of the U6 small nuclear ribonucleoprotein (snRNP) contained an ISL-stabilized A62G mutant of U6 bound to all four RNA-recognition motif (RRM) domains of Prp24 [Montemayor et al...
January 1, 2017: Acta Crystallographica. Section D, Structural Biology
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