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Kara L Norman, Tzu-Chun Chen, Gusti Zeiner, Peter Sarnow
The insulin-induced gene 1 protein (Insig1) inhibits the cholesterol biosynthesis pathway by retaining transcription factor SREBP in the endoplasmic reticulum, and by causing the degradation of HMGCR, the rate-limiting enzyme in cholesterol biosynthesis. Liver-specific microRNA miR-122, on the other hand, enhances cholesterol biosynthesis by an unknown mechanism. We have found that Insig1 mRNAs are generated by alternative cleavage and polyadenylation, resulting in specific isoform mRNA species. During high cholesterol abundance, the short 1...
September 19, 2017: RNA
Olga Herdt, Alexander Neumann, Bernd Timmermann, Florian Heyd
Recent work has identified cancer-associated U2AF35 missense mutations in two zinc-finger (ZnF) domains, but little is known about Q157R/P substitutions within the second ZnF. Surprisingly, we find that the c.470A>G mutation not only leads to the Q157R substitution, but also creates an alternative 5' splice site (ss) resulting in the deletion of four amino acids (Q157Rdel). Q157P, Q157R and Q157Rdel control alternative splicing of distinct groups of exons in cell culture and in human patients, suggesting that missplicing of different targets may contribute to cellular aberrations...
September 11, 2017: RNA
Sebastian Falk, Jan-Niklas Tants, Jerôme Basquin, Matthias Thoms, Ed Hurt, Michael Sattler, Elena Conti
The nuclear exosome and the associated RNA helicase Mtr4 participate in the processing of several ribonucleoprotein particles (RNP), including the maturation of the large ribosomal subunit (60S). S. cerevisiae Mtr4 interacts directly with Nop53, a ribosomal biogenesis factor present in late pre-60S particles containing precursors of the 5.8S rRNA. The Mtr4-Nop53 interaction plays a pivotal role in the maturation of the 5.8S rRNA, providing a physical link between the nuclear exosome and the pre-60S RNP. An analogous interaction between Mtr4 and another ribosome biogenesis factor, Utp18, directs the exosome to an earlier pre-ribosomal particle...
September 7, 2017: RNA
Hiva Azizi, Carole Dumas, Barbara Papadopoulou
Leishmania and other trypanosomatid protozoa lack control at the level of transcription initiation and regulate gene expression exclusively posttranscriptionally. We have reported previously that Leishmania harbors a unique class of Short Interspersed DEgenerate Retroposons (SIDERs) that are predominantly located within 3'UTRs and play a major role in posttranscriptional control. We have shown that members of the SIDER2 subfamily initiate mRNA decay through endonucleolytic cleavage within the second conserved 79-nt signature sequence of SIDER2 retroposons...
September 6, 2017: RNA
Bradley P Klemm, Agnes Karasik, Kipchumba J Kaitany, Aranganathan Shanmuganathan, Matthew J Henley, Adam Z Thelen, Allison Jl Dewar, Nathaniel D Jackson, Markos Koutmos, Carol A Fierke
Protein-only ribonuclease P (PRORP) is an enzyme responsible for catalyzing the 5' end maturation of precursor transfer ribonucleic acids (pre-tRNAs) encoded by various cellular compartments in many eukaryotes. PRORPs from plants act as single-subunit enzymes and have been used as a model system for analyzing the function of the metazoan PRORP nuclease subunit, which requires two additional proteins for efficient catalysis. There are currently few molecular details known about the PRORP-pre-tRNA complex. Here, we characterize the determinants of substrate recognition by the single subunit Arabidopsis thaliana PRORP1 and PRORP2 using kinetic and thermodynamic experiments...
September 5, 2017: RNA
Penghui Bao, Claudia Höbartner, Klaus Hartmuth, Reinhard Lührmann
The RNA helicase Prp2 facilitates the remodelling of the spliceosomal B(act) complex to the catalytically activated B* complex just before step one of splicing. As a high-resolution cryo-EM structure of the B* complex is currently lacking, the precise spliceosome remodelling events mediated by Prp2 remain poorly understood. To investigate the latter, we used chemical structure probing to compare the RNA structure of purified yeast B(act) and B* complexes. Our studies reveal deviations from conventional RNA helices in the functionally important U6 snRNA internal stem loop and U2/U6 helix Ib in the activated B(act) complex, and to a lesser extent in B*...
September 1, 2017: RNA
Kang He, Yang Sun, Huamei Xiao, Chang Ge, Fei Li, Zhaojun Han
The accurate rise and fall of active hormones is important for insect development. The ecdysteroids must be cleared in a timely manner. However, the mechanism of supressing the ecdysteroid biosynthesis at the right time remains unclear. Here, we sequenced a small RNA library of Chilo suppressalis and identified 300 miRNAs in this notorious rice insect pest. Microarray analysis yielded 54 differentially expressed miRNAs during metamorphosis development. Target prediction and in vitro dual luciferase assays confirmed that seven miRNAs (two conserved and five novel miRNAs) jointly targeted three Halloween genes in the ecdysteroid biosynthesis pathway...
August 31, 2017: RNA
Roopa Comandur, Erik D Olson, Karin Musier-Forsyth
Human tRNA(Lys3) serves as the primer for reverse transcription in human immunodeficiency virus type-1 (HIV-1) and anneals to the complementary primer binding site (PBS) in the genome. All tRNA(Lys) isoacceptors interact with human lysyl-tRNA synthetase (hLysRS) and are selectively packaged into virions. tRNA(Lys3) must be released from hLysRS in order to anneal to the PBS and this process is proposed to be facilitated by the interaction of hLysRS with a tRNA-like element (TLE) first identified in the HIV-1 5'-untranslated region (5'-UTR) of the subtype B NL4-3 virus...
August 31, 2017: RNA
Nicky Jonkhout, Julia Tran, Martin Alexander Smith, Nicole Schonrock, John S Mattick, Eva Maria Novoa
RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs and snoRNAs. This view has changed dramatically in the recent years, to a large extent as a result of systematic efforts to map and quantify various RNA modifications in a transcriptome-wide manner, revealing that RNA modifications are reversible, dynamically regulated, far more widespread than originally thought, and involved in major biological processes, including cell differentiation, sex determination and stress responses...
August 30, 2017: RNA
Xiaochuan Liu, Jaime Freitas, Dinghai Zheng, Mainul Hoque, Marta S Oliveira, Torcato Martins, Telmo Henriques, Bin Tian, Alexandra Moreira
Alternative cleavage and polyadenylation (APA) is a mechanism that generates multiple mRNA isoforms with different 3'UTRs and/or coding sequences from a single gene. Here using 3' Region Extraction And Deep Sequencing (3'READS), we have systematically mapped cleavage and polyadenylation sites (PASs) in Drosophila melanogaster, expanding the total repertoire of PASs previously identified for the species, especially those located in A-rich genomic sequences. cis-element analysis revealed distinct sequence motifs around fly PASs as compared to mammalian ones, including the greater enrichment of upstream UAUA elements and the less prominent presence of downstream UGUG elements...
August 29, 2017: RNA
Margaret A Nakamoto, Alexander F Lovejoy, Alicja M Cygan, John C Boothroyd
RNA contains over 100 modified nucleotides that are created post-transcriptionally, among which pseudouridine (Ψ) is one of the most abundant. Although it was one of the first modifications discovered, the biological role of this modification is still not fully understood. Recently, we reported that a pseudouridine synthase (TgPUS1) is necessary for differentiation of the single-celled eukaryotic parasite Toxoplasma gondii from active to chronic infection. To better understand the biological role of pseudouridylation we report here gel-based and deep-sequencing methods to identify TgPUS1-dependent Ψs in Toxoplasma RNA, and the use of TgPUS1 mutants to examine the effect of this modification on mRNAs...
August 29, 2017: RNA
Thomas Sbarrato, Ruth V Spriggs, Lindsay Wilson, Carolyn Jones, Kate Dudek, Amandine Bastide, Xavier Pichon, Tuija Pöyry, Anne E Willis
Translational regulation plays a central role in the global gene expression of a cell and detection of such regulation has allowed deciphering of critical biological mechanisms. Genome-wide studies of the regulation of translation (translatome) performed on microarrays represent a substantial proportion of studies, alongside with recent advances in deep-sequencing methods. However, there has been a lack of development in specific processing methodologies that deal with the distinct nature of translatome array data...
August 25, 2017: RNA
Ildar Gainetdinov, Yulia Skvortsova, Sofia Kondratieva, Sergey Funikov, Tatyana Azhikina
PIWI proteins and their partner small RNAs, termed piRNAs, are known to control transposable elements (TEs) in the germline. Here, we provide evidence that in humans this control is exerted in two different modes. On the one hand, production of piRNAs specifically targeting evolutionarily youngest TEs (L1HS, L1PA2-L1PA6, LTR12C, SVA) is present both at prenatal and postnatal stages of spermatogenesis and is performed without involvement of piRNA clusters. On the other hand, at postnatal stages, piRNAs deriving from pachytene clusters target "older" TEs and thus complement cluster-independent piRNA production to achieve relevant targeting of virtually all TEs expressed in postnatal testis...
August 25, 2017: RNA
Wael Kamel, Göran Akusjärvi
Here we show that the adenovirus major late promoter produces a 31-nucleotide transcriptional start site small RNA (MLP-TSS-sRNA) that retains the 7-methylguanosine (m7G)-cap and is incorporated onto Ago2-containing RNA-induced silencing complexes (RISC) in human adenovirus-37 infected cells. RNA polymerase II CLIP (UV-cross linking immunoprecipitation) experiments suggest that the MLP-TSS-sRNA is produced by promoter proximal stalling/termination of RNA polymerase II transcription at the site of the small RNA 3'end...
August 24, 2017: RNA
Benjamin Soibam
Super-enhancers are characterized by high levels of Mediator binding and are major contributors to the expression of their associated genes. They exhibit high levels of local chromatin interactions and higher order of local chromatin organization. On the other hand, LncRNAs can localize to specific DNA sites by forming a RNA:DNA:DNA triplex, which in turn can contribute to local chromatin organization. In this paper, we characterize a new class of lncRNAs called super-lncRNAs that target super-enhancers and which can contribute to the local chromatin organization of the super-enhancers...
August 24, 2017: RNA
Ana Marques-Ramos, Marco M Candeias, Juliane Menezes, Rafaela Lacerda, Margaret Willcocks, Alexandre Teixeira, Nicolas Locker, Luisa Romao
The mechanistic/mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that integrates cellular signals from the nutrient and energy status to act, namely, on the protein synthesis machinery. While major advances have emerged regarding the regulators and effects of mTOR signaling pathway, little is known about the regulation of mTOR gene expression. Here, we show that human mTOR transcript can be translated in a cap-independent manner, and that its 5' untranslated region (UTR) is a highly folded RNA scaffold capable of binding directly to the 40S ribosomal subunit...
August 18, 2017: RNA
Kaitlyn M Holman, Anupama K Puppala, Jonathan W Lee, Hyun Lee, Miljan Simonovic
Seryl-tRNA synthetase (SerRS) attaches L-serine to the cognate serine tRNA (tRNA(Ser)) and the non-cognate selenocysteine tRNA (tRNA(Sec)). The latter activity initiates the anabolic cycle of selenocysteine (Sec), proper decoding of an in-frame Sec UGA codon, and synthesis of selenoproteins across all domains of life. While the accuracy of SerRS is important for overall proteome integrity, it is its substrate promiscuity that is vital for the integrity of the selenoproteome. This raises a question as to what elements in the two tRNA species, harboring different anticodon sequences and adopting distinct folds, facilitate aminoacylation by a common aminoacyl-tRNA synthetase...
August 14, 2017: RNA
Jesse Donovan, Sneha Rath, David Kolet-Mandrikov, Alexei Korennykh
Mammalian cells respond to double-stranded RNA (dsRNA) by activating a translation-inhibiting endoribonuclease, RNase L. Consensus in the field indicates that RNase L arrests protein synthesis by degrading ribosomal RNAs (rRNAs) and messenger RNAs (mRNAs). However, here we provide evidence for a different and far more efficient mechanism. By sequencing abundant RNA fragments generated by RNase L in human cells, we identify site-specific cleavage of two groups of non-coding RNAs: Y-RNAs, whose function is poorly understood, and cytosolic tRNAs, which are essential for translation...
August 14, 2017: RNA
Suzanne M McDermott, Kenneth Stuart
Uridine insertion and deletion RNA editing generates functional mitochondrial mRNAs in Trypanosoma brucei, and several transcripts are differentially edited in bloodstream (BF) and procyclic form (PF) cells correlating with changes in mitochondrial function. Editing is catalyzed by three ∼20S editosomes that have a common set of 12 proteins, but are typified by mutually exclusive RNase III KREN1, N2, and N3 endonucleases with distinct cleavage specificities. KREPB4 is a common editosome protein that has a degenerate RNase III domain lacking conserved catalytic residues, in addition to zinc-finger and Pumilio/fem-3 mRNA binding factor (PUF) motifs...
August 11, 2017: RNA
Jun Cheng, Kerstin C Maier, Ziga Avsec, Petra Rus, Julien Gagneur
The stability of mRNA is one of the major determinants of gene expression. Although a wealth of sequence elements regulating mRNA stability has been described, their quantitative contributions to half-life are unknown. Here, we built a quantitative model for Saccharomyces cerevisiae based on functional mRNA sequence features that explains 59% of the half-life variation between genes and predicts half-life at a median relative error of 30%. The model revealed a new destabilizing 3'UTR motif, ATATTC, which we functionally validated...
August 11, 2017: RNA
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