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https://www.readbyqxmd.com/read/29768215/mechanism-of-nonsense-mediated-mrna-decay-stimulation-by-splicing-factor-srsf1
#1
Isabel Aznarez, Tomoki T Nomakuchi, Jaclyn Tetenbaum-Novatt, Mohammad Alinoor Rahman, Oliver Fregoso, Holly Rees, Adrian R Krainer
The splicing factor SRSF1 promotes nonsense-mediated mRNA decay (NMD), a quality control mechanism that degrades mRNAs with premature termination codons (PTCs). Here we show that transcript-bound SRSF1 increases the binding of NMD factor UPF1 to mRNAs while in, or associated with, the nucleus, bypassing UPF2 recruitment and promoting NMD. SRSF1 promotes NMD when positioned downstream of a PTC, which resembles the mode of action of exon junction complex (EJC) and NMD factors. Moreover, splicing and/or EJC deposition increase the effect of SRSF1 on NMD...
May 15, 2018: Cell Reports
https://www.readbyqxmd.com/read/29712837/mechanistic-studies-of-a-small-molecule-modulator-of-smn2-splicing
#2
Jingxin Wang, Peter G Schultz, Kristen A Johnson
RG-7916 is a first-in-class drug candidate for the treatment of spinal muscular atrophy (SMA) that functions by modulating pre-mRNA splicing of the SMN2 gene, resulting in a 2.5-fold increase in survival of motor neuron (SMN) protein level, a key protein lacking in SMA patients. RG-7916 is currently in three interventional phase 2 clinical trials for various types of SMA. In this report, we show that SMN-C2 and -C3, close analogs of RG-7916, act as selective RNA-binding ligands that modulate pre-mRNA splicing...
April 30, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29684192/the-exon-intron-gene-structure-upstream-of-the-initiation-codon-predicts-translation-efficiency
#3
Chun Shen Lim, Samuel J T Wardell, Torsten Kleffmann, Chris M Brown
Introns in mRNA leaders are common in complex eukaryotes, but often overlooked. These introns are spliced out before translation, leaving exon-exon junctions in the mRNA leaders (leader EEJs). Our multi-omic approach shows that the number of leader EEJs inversely correlates with the main protein translation, as does the number of upstream open reading frames (uORFs). Across the five species studied, the lowest levels of translation were observed for mRNAs with both leader EEJs and uORFs (29%). This class of mRNAs also have ribosome footprints on uORFs, with strong triplet periodicity indicating uORF translation...
April 19, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29653229/the-splicing-of-tiny-introns-of-paramecium-is-controlled-by-mago
#4
Julia Contreras, Victoria Begley, Laura Marsella, Eduardo Villalobo
The exon junction complex (EJC) is a key element of the splicing machinery. The EJC core is composed of eIF4A3, MAGO, Y14 and MLN51. Few accessory proteins, such as CWC22 or UPF3, bind transiently to the EJC. The EJC has been implicated in the control of the splicing of long introns. To ascertain whether the EJC controls the splicing of short introns, we used Paramecium tetraurelia as a model organism, since it has thousands of very tiny introns. To elucidate whether EJC affects intron splicing in P. tetraurelia, we searched for EJC protein-coding genes, and silenced those genes coding for eIF4A3, MAGO and CWC22...
April 10, 2018: Gene
https://www.readbyqxmd.com/read/29561870/multispecies-reconstructions-uncover-widespread-conservation-and-lineage-specific-elaborations-in-eukaryotic-mrna-metabolism
#5
Bridget P Bannerman, Susanne Kramer, Richard G Dorrell, Mark Carrington
The degree of conservation and evolution of cytoplasmic mRNA metabolism pathways across the eukaryotes remains incompletely resolved. In this study, we describe a comprehensive genome and transcriptome-wide analysis of proteins involved in mRNA maturation, translation, and mRNA decay across representative organisms from the six eukaryotic super-groups. We demonstrate that eukaryotes share common pathways for mRNA metabolism that were almost certainly present in the last eukaryotic common ancestor, and show for the first time a correlation between intron density and a selective absence of some Exon Junction Complex (EJC) components in eukaryotes...
2018: PloS One
https://www.readbyqxmd.com/read/29529047/high-resolution-detection-of-chromosomal-rearrangements-in-leukemias-through-mate-pair-whole-genome-sequencing
#6
Anh Nhi Tran, Fulya Taylan, Vasilios Zachariadis, Ingegerd Ivanov Öfverholm, Anna Lindstrand, Francesco Vezzi, Britta Lötstedt, Magnus Nordenskjöld, Ann Nordgren, Daniel Nilsson, Gisela Barbany
The detection of recurrent somatic chromosomal rearrangements is standard of care for most leukemia types. Even though karyotype analysis-a low-resolution genome-wide chromosome analysis-is still the gold standard, it often needs to be complemented with other methods to increase resolution. To evaluate the feasibility and applicability of mate pair whole genome sequencing (MP-WGS) to detect structural chromosomal rearrangements in the diagnostic setting, we sequenced ten bone marrow samples from leukemia patients with recurrent rearrangements...
2018: PloS One
https://www.readbyqxmd.com/read/29528287/ice1-promotes-the-link-between-splicing-and-nonsense-mediated-mrna-decay
#7
Thomas D Baird, Ken Chih-Chien Cheng, Yu-Chi Chen, Eugen Buehler, Scott E Martin, James Inglese, J Robert Hogg
The nonsense-mediated mRNA decay (NMD) pathway detects aberrant transcripts containing premature termination codons (PTCs) and regulates expression of 5-10% of non-aberrant human mRNAs. To date, most proteins involved in NMD have been identified by genetic screens in model organisms; however, the increased complexity of gene expression regulation in human cells suggests that additional proteins may participate in the human NMD pathway. To identify proteins required for NMD, we performed a genome-wide RNAi screen against >21,000 genes...
March 12, 2018: ELife
https://www.readbyqxmd.com/read/29490687/genetic-ablation-of-dynactin-p150-glued-in-postnatal-neurons-causes-preferential-degeneration-of-spinal-motor-neurons-in-aged-mice
#8
Jia Yu, Chen Lai, Hoon Shim, Chengsong Xie, Lixin Sun, Cai-Xia Long, Jinhui Ding, Yan Li, Huaibin Cai
BACKGROUND: Dynactin p150Glued , the largest subunit of the dynactin macromolecular complex, binds to both microtubules and tubulin dimers through the N-terminal cytoskeleton-associated protein and glycine-rich (CAP-Gly) and basic domains, and serves as an anti-catastrophe factor in stabilizing microtubules in neurons. P150Glued also initiates dynein-mediated axonal retrograde transport. Multiple missense mutations at the CAP-Gly domain of p150Glued are associated with motor neuron diseases and other neurodegenerative disorders, further supporting the importance of microtubule domains (MTBDs) in p150Glued functions...
March 1, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29467783/a-genomic-view-of-alternative-splicing-of-long-non-coding-rnas-during-rice-seed-development-reveals-extensive-splicing-and-lncrna-gene-families
#9
Edward A Kiegle, Alex Garden, Elia Lacchini, Martin M Kater
Alternative splicing (AS) is a key modulator of development in many eukaryotic organisms. In plants, alternative splice forms of non-coding RNAs (ncRNAs) are known to modulate flowering time in Arabidopsis and fertility in rice. Here we demonstrate that alternative splicing of coding and long non-coding RNAs occurs during rice seed development by comparing AS in immature seeds vs. embryo and endosperm of mature seeds. Based on computational predictions of AS events determined from a Bayesian analysis of junction counts of RNA-seq datasets, differential splicing of protein-coding, and non-coding RNAs was determined...
2018: Frontiers in Plant Science
https://www.readbyqxmd.com/read/29366779/splicing-activator-rnps1-suppresses-errors-in-pre-mrna-splicing-a-key-factor-for-mrna-quality-control
#10
Kazuhiro Fukumura, Kunio Inoue, Akila Mayeda
Human RNPS1 protein was first identified as a pre-mRNA splicing activator in vitro and RNPS1 regulates alternative splicing in cellulo. RNPS1 was also known as a peripheral factor of the exon junction complex (EJC). Here we show that cellular knockdown of RNPS1 induced a reduction of the wild-type aurora kinase B (AURKB) protein due to the induced aberrant pre-mRNA splicing events, indicating that the fidelity of AURKB pre-mRNA splicing was reduced. The major aberrant AURKB mRNA was derived from the upstream pseudo 5' and 3' splice sites in intron 5, which resulted in the production of the non-functional truncated AURKB protein...
February 12, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29351963/the-exon-junction-complex-structural-insights-into-a-faithful-companion-of-mammalian-mrnps
#11
REVIEW
Jennifer V Gerbracht, Niels H Gehring
During splicing, the exon junction complex (EJC) is deposited upstream of exon-exon boundaries. The EJC and its peripheral bound proteins play an essential role in mediating mRNA export, translation and turnover. However, the exact sequence of EJC assembly and the involved factors during splicing remain elusive. Recently published structures of the human C* spliceosome clarified the position of the EJC at this phase of splicing and have given insight into previously unidentified interactions between the EJC and spliceosomal proteins...
February 19, 2018: Biochemical Society Transactions
https://www.readbyqxmd.com/read/29330450/c-terminal-short-arginine-serine-repeat-sequence-dependent-regulation-of-y14-rbm8a-localization
#12
Takanori Tatsuno, Yasuhito Ishigaki
Y14 (RBM8A) is an RNA recognition motif-containing protein that forms heterodimers with MAGOH and serves as a core factor of the RNA surveillance machinery for the exon junction complex (EJC). The role of the Y14 C-terminal serine/arginine (RS) repeat-containing region, which has been reported to undergo modifications such as phosphorylation and methylation, has not been sufficiently investigated. Thus, we aimed to explore the functional significance of the Y14 C-terminal region. Deletion or dephosphorylation mimic mutants of the C-terminal region showed a shift in localization from the nucleoplasmic region; in addition, the C-terminal RS repeat-containing sequence itself exhibited the potential for nucleolar localization...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29222161/detection-of-proteome-diversity-resulted-from-alternative-splicing-is-limited-by-trypsin-cleavage-specificity
#13
Xiaojing Wang, Simona G Codreanu, Bo Wen, Kai Li, Matthew C Chambers, Daniel C Liebler, Bing Zhang
Alternative splicing dramatically increases transcriptome complexity but its contribution to proteome diversity remains controversial. Exon-exon junction spanning peptides provide direct evidence for the translation of specific splice isoforms and are critical for delineating protein isoform complexity. Here we found that junction-spanning peptides are underrepresented in publicly available mass spectrometry-based shotgun proteomics data sets. Further analysis showed that evolutionarily conserved preferential nucleotide usage at exon boundaries increases the occurrence of lysine- and arginine-coding triplets at the end of exons...
March 2018: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/29212664/genetic-bypass-of-essential-rna-repair-enzymes-in-budding-yeast
#14
Patrick D Cherry, Laura K White, Kerri York, Jay R Hesselberth
RNA repair enzymes catalyze rejoining of an RNA molecule after cleavage of phosphodiester linkages. RNA repair in budding yeast is catalyzed by two separate enzymes that process tRNA exons during their splicing and HAC1 mRNA exons during activation of the unfolded protein response (UPR). The RNA ligase Trl1 joins 2',3'-cyclic phosphate and 5'-hydroxyl RNA fragments, creating a phosphodiester linkage with a 2'-phosphate at the junction. The 2'-phosphate is removed by the 2'-phosphotransferase Tpt1. We bypassed the essential functions of TRL1 and TPT1 in budding yeast by expressing "prespliced," intronless versions of the 10 normally intron-containing tRNAs, indicating this repair pathway does not have additional essential functions...
March 2018: RNA
https://www.readbyqxmd.com/read/29206898/somatic-mutation-footprinting-reveals-a-unique-tetranucleotide-signature-associated-with-intron-exon-boundaries-in-lung-cancer
#15
Samuel Wormald, Anita Lerch, Dmitri Mouradov, Liam O'Connor
Cigarette smoke comprises a large number of carcinogenic substances that can increase DNA mutation load in epithelial cells of the mouth, throat and lungs. While a strong C:A substitution preference is abundant in tobacco-related cancer genomes, detection of complex or less abundant somatic mutation signatures may be confounded by the heterogeneity of carcinogens present in smoke. Trinucleotide signatures are defined for a variety of somatic mutation processes, yet the extent to which this configuration optimally defines and discriminates between mutational processes is not clear...
February 9, 2018: Carcinogenesis
https://www.readbyqxmd.com/read/29190905/the-exon-38-containing-arhgef11-splice-isoform-is-differentially-expressed-and-is-required-for-migration-and-growth-in-invasive-breast-cancer-cells
#16
Masahiko Itoh, Derek C Radisky, Masaaki Hashiguchi, Hiroyuki Sugimoto
Breast cancer invasion involves the loss of cell-cell junctions and acquisition of an invasive, migratory phenotype, and breast cancer cells of the basal intrinsic subtype are more invasive and metastatic than breast cancer cells of other subtypes. ARHGEF11 is a RhoGEF that was previously shown to bind to the tight junction protein ZO-1 at perijunctional actomyosin ring (PJAR), a network of cortically organized actin and myosin filaments associated with junctional complexes that regulates cell-cell adhesion and polarization...
November 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29183387/nanopore-sequencing-of-full-length-brca1-mrna-transcripts-reveals-co-occurrence-of-known-exon-skipping-events
#17
Lucy C de Jong, Simone Cree, Vanessa Lattimore, George A R Wiggins, Amanda B Spurdle, Allison Miller, Martin A Kennedy, Logan C Walker
BACKGROUND: Laboratory assays evaluating the effect of DNA sequence variants on BRCA1 mRNA splicing may contribute to classification by providing molecular evidence. However, our knowledge of normal and aberrant BRCA1 splicing events to date has been limited to data derived from assays targeting partial transcript sequences. This study explored the utility of nanopore sequencing to examine whole BRCA1 mRNA transcripts and to provide accurate categorisation of in-frame and out-of-frame splicing events...
November 28, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29153833/structure-of-the-post-catalytic-spliceosome-from-saccharomyces-cerevisiae
#18
Rui Bai, Chuangye Yan, Ruixue Wan, Jianlin Lei, Yigong Shi
Removal of an intron from a pre-mRNA by the spliceosome results in the ligation of two exons in the post-catalytic spliceosome (known as the P complex). Here, we present a cryo-EM structure of the P complex from Saccharomyces cerevisiae at an average resolution of 3.6 Å. The ligated exon is held in the active site through RNA-RNA contacts. Three bases at the 3' end of the 5' exon remain anchored to loop I of U5 small nuclear RNA, and the conserved AG nucleotides of the 3'-splice site (3'SS) are specifically recognized by the invariant adenine of the branch point sequence, the guanine base at the 5' end of the 5'SS, and an adenine base of U6 snRNA...
December 14, 2017: Cell
https://www.readbyqxmd.com/read/29151891/the-exon-junction-complex-factor-y14-is-dynamic-in-the-nucleus-of-the-beetle-tribolium-castaneum-during-late-oogenesis
#19
Artem M Kiselev, Irina S Stepanova, Leonid S Adonin, Florina M Batalova, Vladimir N Parfenov, Dmitry S Bogolyubov, Olga I Podgornaya
Background: The oocyte chromosomes of the red flour beetle, Tribolium castaneum , are gathered into a knot, forming a karyosphere at the diplotene stage of meiotic prophase. Chromatin rearrangement, which is a characteristic feature of oocyte maturation, is well documented. The T. castaneum karyosphere is surrounded by a complex extrachromosomal structure termed the karyosphere capsule. The capsule contains the vast majority of oocyte RNA. We have previously shown using a BrUTP assay that oocyte chromosomes in T...
2017: Molecular Cytogenetics
https://www.readbyqxmd.com/read/29052934/the-contribution-of-alternative-splicing-to-genetic-risk-for-psychiatric-disorders
#20
REVIEW
E Reble, A Dineen, C L Barr
A genetic contribution to psychiatric disorders has clearly been established and genome-wide association studies now provide the location of risk genes and genetic variants associated with risk. However, the mechanism by which these genes and variants contribute to psychiatric disorders is mostly undetermined. This is in part because non-synonymous protein coding changes cannot explain the majority of variants associated with complex genetic traits. Based on this, it is predicted that these variants are causing gene expression changes, including changes to alternative splicing...
October 20, 2017: Genes, Brain, and Behavior
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