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Hu Li, Fuling Wang, Yonghua Fei, Yanhua Lei, Fengxiang Lu, Ping Guo, Wei Li, Xuehong Xun
The aim of the present study was to investigate the key genes, miRNAs and pathways in hypopharyngeal squamous cell carcinoma (HPSCC) and to elucidate the mechanisms underlying HPSCC development. The gene and microRNA (miRNA) expression profiles of HPSCC tissues and adjacent normal tissues from three subjects were obtained. Differentially expressed genes (DEGs) and differentially expressed miRNAs were identified in HPSCC. Functional annotation and protein‑protein interaction (PPI) network were conducted to elucidate the biological functions of DEGs...
June 19, 2018: Oncology Reports
Phillip L Price, Dmytro Morderer, Wilfried Rossoll
Spinal muscular atrophy (SMA) is a motor neuron disease caused by mutations/deletions within the survival of motor neuron 1 (SMN1) gene that lead to a pathological reduction of SMN protein levels. SMN is part of a multiprotein complex, functioning as a molecular chaperone that facilitates the assembly of spliceosomal small nuclear ribonucleoproteins (snRNP). In addition to its role in spliceosome formation, SMN has also been found to interact with mRNA-binding proteins (mRBPs), and facilitate their assembly into mRNP transport granules...
2018: Advances in Neurobiology
Markus T Bohnsack, Katherine E Sloan
Modifications in cellular RNAs have emerged as key regulators of all aspects of gene expression, including pre-mRNA splicing. During spliceosome assembly and function, the small nuclear RNAs (snRNAs) form numerous dynamic RNA-RNA and RNA-protein interactions, which are required for spliceosome assembly, correct positioning of the spliceosome on substrate pre-mRNAs and catalysis. The human snRNAs contain several base methylations as well as a myriad of pseudouridines and 2'-O-methylated nucleotides, which are largely introduced by small Cajal body-specific-RNPs...
June 1, 2018: Biological Chemistry
Guosheng Qu, Carol Lyn Piazza, Dorie Smith, Marlene Belfort
Group II introns are mobile ribozymes that are rare in bacterial genomes, often cohabiting with various mobile elements, and seldom interrupting housekeeping genes. What accounts for this distribution has not been well understood. Here, we demonstrate that Ll.LtrB, the group II intron residing in a relaxase gene on a conjugative plasmid from Lactococcus lactis , inhibits its host gene expression and restrains the naturally cohabiting mobile element from conjugative horizontal transfer. We show that reduction in gene expression is mainly at the mRNA level, and results from the interaction between exon-binding sequences (EBSs) in the intron and intron-binding sequences (IBSs) in the mRNA...
June 15, 2018: ELife
Lydia Herzel, Korinna Straube, Karla M Neugebauer
Pre-mRNA splicing is accomplished by the spliceosome, a megadalton complex that assembles de novo on each intron. Because spliceosome assembly and catalysis occur cotranscriptionally, we hypothesized that introns are removed in the order of their transcription in genomes dominated by constitutive splicing. Remarkably little is known about splicing order and the regulatory potential of nascent transcript remodeling by splicing, due to the limitations of existing methods that focus on analysis of mature splicing products (mRNAs) rather than substrates and intermediates...
June 14, 2018: Genome Research
Giulia Pianigiani, Danilo Licastro, Paola Fortugno, Daniele Castiglia, Ivana Petrovic, Franco Pagani
MicroRNAs are found throughout the genome and are processed by the microprocessor complex (MPC) from longer precursors. Some precursor miRNAs overlap intron:exon junctions. These Splice site Overlapping microRNAs (SO-miRNAs) are mostly located in coding genes. It has been intimated, in the rarer examples of SO-miRNAs in non-coding RNAs, that the competition between the spliceosome and the MPC modulates alternative splicing. However, the effect of this overlap on coding transcripts is unknown. Unexpectedly, we show that neither Drosha silencing nor SF3b1 silencing changed the inclusion ratio of SO-miRNA exons...
June 12, 2018: RNA
Chris C R Smith, Silas Tittes, J Paul Mendieta, Erin Collier-Zans, Heather C Rowe, Loren H Rieseberg, Nolan C Kane
Alternative splicing enables organisms to produce the diversity of proteins necessary for multicellular life by using relatively few protein-coding genes. Although differences in splicing have been identified among divergent taxa, the shorter-term evolution of splicing is understudied. The origins of novel splice forms, and the contributions of alternative splicing to major evolutionary transitions, are largely unknown. This study used transcriptomes of wild and domesticated sunflowers to examine splice differentiation and regulation during domestication...
June 11, 2018: Proceedings of the National Academy of Sciences of the United States of America
Lorenzo Casalino, Giulia Palermo, Angelo Spinello, Ursula Rothlisberger, Alessandra Magistrato
The spliceosome (SPL) is a majestic macromolecular machinery composed of five small nuclear RNAs and hundreds of proteins. SPL removes noncoding introns from precursor messenger RNAs (pre-mRNAs) and ligates coding exons, giving rise to functional mRNAs. Building on the first SPL structure solved at near-atomic-level resolution, here we elucidate the functional dynamics of the intron lariat spliceosome (ILS) complex through multi-microsecond-long molecular-dynamics simulations of ∼1,000,000 atoms models. The ILS essential dynamics unveils ( i ) the leading role of the Spp42 protein, which heads the gene maturation by tuning the motions of distinct SPL components, and ( ii ) the critical participation of the Cwf19 protein in displacing the intron lariat/U2 branch helix...
June 11, 2018: Proceedings of the National Academy of Sciences of the United States of America
Kiyonaga Fujii, Yuka Miyata, Ikuya Takahashi, Hirotaka Koizumi, Hisashi Saji, Masahiro Hoshikawa, Masayuki Takagi, Toshihide Nishimura, Haruhiko Nakamura
PURPOSE: The molecular underpinnings that may prognosticate survival and increase our understanding of tumor development and progression are still poorly understood. This study aimed to define the molecular signatures for malignancy in small cell lung carcinoma (SCLC), which is known for its highly aggressive clinical features and poor prognosis. EXPERIMENTAL DESIGN: Using clinical specimens, we performed a comparative proteomic analysis of high-grade SCLCs and low-grade pulmonary carcinoid tumors (PCTs), both of which are types of neuroendocrine tumors...
June 11, 2018: Proteomics. Clinical Applications
Gert Weber, Gregory T DeKoster, Nicole Holton, Kathleen B Hall, Markus C Wahl
The first RNA recognition motif of the Drosophila SNF protein is an example of an RNA binding protein with multi-specificity. It binds different RNA hairpin loops in spliceosomal U1 or U2 small nuclear RNAs, and only in the latter case requires the auxiliary U2A' protein. Here we investigate its functions by crystal structures of SNF alone and bound to U1 stem-loop II, U2A' or U2 stem-loop IV and U2A', SNF dynamics from NMR spectroscopy, and structure-guided mutagenesis in binding studies. We find that different loop-closing base pairs and a nucleotide exchange at the tips of the loops contribute to differential SNF affinity for the RNAs...
June 7, 2018: Nature Communications
Yusuke Shiozawa
Splicing factor mutations represent a novel class of driver mutations in myelodysplastic syndromes, where four genes, including SF3B1, SRSF2, U2AF1, and ZRSR2, are most frequently affected. SF3B1 and SRSF2 mutations show prominent specificity to the syndrome subtypes characterized by increased ring sideroblasts and chronic myelomonocytic leukemia, respectively. These mutations are suspected to be involved in the pathogenesis of the above mentioned syndromes most likely via abnormal RNA splicing. However, the precise mechanism and target genes have not been fully understood...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Helena Chaytow, Yu-Ting Huang, Thomas H Gillingwater, Kiterie M E Faller
Ever since loss of survival motor neuron (SMN) protein was identified as the direct cause of the childhood inherited neurodegenerative disorder spinal muscular atrophy, significant efforts have been made to reveal the molecular functions of this ubiquitously expressed protein. Resulting research demonstrated that SMN plays important roles in multiple fundamental cellular homeostatic pathways, including a well-characterised role in the assembly of the spliceosome and biogenesis of ribonucleoproteins. More recent studies have shown that SMN is also involved in other housekeeping processes, including mRNA trafficking and local translation, cytoskeletal dynamics, endocytosis and autophagy...
June 5, 2018: Cellular and Molecular Life Sciences: CMLS
Meemanage D De Zoysa, Guowei Wu, Raviv Katz, Yi-Tao Yu
Box H/ACA RNAs are a group of small RNAs found in abundance in eukaryotes (as well as in archaea). Although their sequences differ, eukaryotic box H/ACA RNAs all share the same unique hairpin-hinge-hairpin-tail structure. Almost all of them function as guides that primarily direct pseudouridylation of rRNAs and spliceosomal snRNAs at specific sites. Although box H/ACA RNA-guided pseudouridylation has been extensively studied, the detailed rules governing this reaction, especially those concerning the guide RNA-substrate RNA base-pairing interactions that determine the specificity and efficiency of pseudouridylation, are still not exactly clear...
June 5, 2018: RNA
Sushmita Poddar, Pei She Loh, Zi Hao Ooi, Farhana Osman, Joachim Eul, Volker Patzel
Spliceosome-mediated RNA trans-splicing enables correction or labeling of pre-mRNA, but therapeutic applications are hampered by issues related to the activity and target specificity of trans-splicing RNA (tsRNA). We employed computational RNA structure design to improve both on-target activity and specificity of tsRNA in a herpes simplex virus thymidine kinase/ganciclovir suicide gene therapy approach targeting alpha fetoprotein (AFP), a marker of hepatocellular carcinoma (HCC) or human papillomavirus type 16 (HPV-16) pre-mRNA...
June 1, 2018: Molecular Therapy. Nucleic Acids
Abigail Read, Rachael Natrajan
Breast cancer is known to be a heterogeneous disease driven by a large repertoire of molecular abnormalities, which contribute to its diverse clinical behavior. Despite the success of targeted therapy approaches for breast cancer patient management, there is still a lack of the molecular understanding of aggressive forms of the disease and clinical management of these patients remains difficult. The advent of high throughput sequencing technologies, have paved the way for a more complete understanding of the molecular make-up of the breast cancer genome...
May 30, 2018: Endocrine-related Cancer
Diego M Marzese, Ayla O Manughian-Peter, Javier I J Orozco, Dave S B Hoon
Metastatic cells exhibit an extraordinary phenotypic plasticity, not only in adapting to unfamiliar microenvironments but also in surviving aggressive treatments and immune responses. A major source of phenotypic variability is alternative splicing (AS) of the pre-messenger RNA. This process is catalyzed by one of the most complex pieces of cellular molecular regulatory events, the spliceosome, which is composed of ribonucleoproteins and polypeptides termed spliceosome factors. With strong evidence indicating that AS affects nearly all genes encoded by the human genome, aberrant AS programs have a significant impact on cancer cell development and progression...
May 29, 2018: Clinical & Experimental Metastasis
Gang Wu, Liying Fan, Michael N Edmondson, Timothy Shaw, Kristy Boggs, John Easton, Michael C Rusch, Thomas R Webb, Jinghui Zhang, Philip M Potter
The recent identification of compounds that interact the spliceosome (sudemycins, spliceostatin A, and meamycin) indicate that these molecules modulate alternative splicing via SF3B1 inhibition. Through whole transcriptome sequencing, we have demonstrated that treatment of Rh18 cells with sudemycin leads to exon skipping as the predominant aberrant splicing event. This was also observed following reanalysis of published RNAseq datasets derived from Hela cells after spliceostatin A exposure. These results are in contrast to previous reports that indicate that intron retention was the major consequence of SF3B1 inhibition...
May 29, 2018: RNA
Andreas J Stroehlein, Neil D Young, Pasi K Korhonen, Ross S Hall, Aaron R Jex, Bonnie L Webster, David Rollinson, Paul J Brindley, Robin B Gasser
BACKGROUND: Blood flukes of the genus Schistosoma cause schistosomiasis-a neglected tropical disease (NTD) that affects more than 200 million people worldwide. Studies of schistosome genomes have improved our understanding of the molecular biology of flatworms, but most of them have focused largely on protein-coding genes. Small non-coding RNAs (sncRNAs) have been explored in selected schistosome species and are suggested to play essential roles in the post-transcriptional regulation of genes, and in modulating flatworm-host interactions...
May 29, 2018: PLoS Neglected Tropical Diseases
Lydia A Hepburn, Angela McHugh, Kenneth Fernandes, Garry Boag, Charlotte M Proby, Irene M Leigh, Mark K Saville
We show that suppression of the spliceosome has potential for the treatment of cutaneous squamous cell carcinoma (cSCC). The small-molecule inhibitors of the spliceosome at the most advanced stage of development target the splicing factor SF3B1/SF3b155. The majority of cSCC cell lines are more sensitive than normal skin cells to death induced by the SF3B1 inhibitor pladienolide B. Knockdown of SF3B1 and a range of other splicing factors with diverse roles in the spliceosome can also selectively kill cSCC cells...
May 1, 2018: Oncotarget
Rui Bai, Ruixue Wan, Chuangye Yan, Jianlin Lei, Yigong Shi
The pre-catalytic spliceosome (B complex) is preceded by the pre-B complex. Here we report the cryo-EM structures of the Saccharomyces cerevisiae pre-B and B complexes at average resolutions of 3.3-4.6 and 3.9 Å, respectively. In the pre-B complex, the duplex between the 5'-splice site (5'SS) and U1 snRNA is recognized by Yhc1, Luc7, and the Sm ring. In the B complex, U1 snRNP is dissociated, the 5'-exon-5'SS sequences are translocated near U6 snRNA, and three B-specific proteins may orient the pre-mRNA. In both complexes, U6 snRNA is anchored to loop I of U5 snRNA and the duplex between the branch point sequence and U2 snRNA is recognized by the SF3b complex...
May 24, 2018: Science
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