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ribosome stall

Mayuki Tanaka, Naoyuki Sotta, Yusuke Yamazumi, Yui Yamashita, Kyoko Miwa, Katsunori Murota, Yukako Chiba, Masami Yokota Hirai, Tetsu Akiyama, Hitoshi Onouchi, Satoshi Naito, Toru Fujiwara
Upstream open reading frames (uORFs) are often translated ahead of the main ORF of a gene and regulate gene expression, sometimes in a condition-dependent manner, but such a role for the minimum uORF (hereafter referred to as 'AUG-stop') in living organisms is currently unclear. Here, we show that AUG-stop plays an important role in the boron (B)-dependent regulation of NIP5;1, encoding a boric acid channel required for normal growth under low B conditions in Arabidopsis thaliana. High B enhanced ribosome stalling at AUG-stop, which was accompanied by the suppression of translation and mRNA degradation...
October 19, 2016: Plant Cell
Xiang Yu, Matthew R Willmann, Stephen J Anderson, Brian D Gregory
RNA turnover is necessary for controlling proper mRNA levels post-transcriptionally. In general, RNA degradation is via exoribonucleases that degrade RNA either from the 5' end to the 3' end, such as XRN4, or in the opposite direction by the multi-subunit exosome complex. Here, we use genome-wide mapping of uncapped and cleaved transcripts to reveal the global landscape of co-translational mRNA decay in the Arabidopsis thaliana transcriptome. We found that this process leaves a clear three nucleotide periodicity in open reading frames...
October 7, 2016: Plant Cell
Cheng-Yu Hou, Wen-Chi Lee, Hsiao-Chun Chou, Ai-Ping Chen, Shu-Jen Chou, Ho-Ming Chen
High-throughput approaches for profiling the 5' ends of RNA degradation intermediates on a genome-wide scale are frequently applied to analyze and validate cleavage sites guided by microRNAs (miRNAs). However, the complexity of the RNA degradome other than miRNA targets is currently largely uncharacterized, and this limits the application of RNA degradome studies. We conducted a global analysis of 5'-truncated mRNA ends that mapped to coding sequences (CDSs) of Arabidopsis (Arabidopsis thaliana), rice (Oryza sativa) and soybean (Glycine max)...
October 14, 2016: Plant Cell
Ilya A Osterman, Ekaterina S Komarova, Dmitry I Shiryaev, Ilya A Korniltsev, Irina M Khven, Dmitry A Lukyanov, Vadim N Tashlitsky, Marina V Serebryakova, Olga V Efremenkova, Yan A Ivanenkov, Alexey A Bogdanov, Petr V Sergiev, Olga A Dontsova
In order to accelerate drug discovery, a simple, reliable and cost-effective system for high-throughput identification of a potential antibiotic mechanism of action is required. To facilitate such screening of new antibiotics, we created a double reporter system for not only antimicrobial activity detection, but also for simultaneous sorting of potential antimicrobials into those that cause ribosome stalling, and others that induce SOS response due to DNA damage. In this reporter system the red fluorescent protein gene rfp was placed under the control of the SOS-inducible sulA promoter...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Sanjay B Hari, Robert T Sauer
In eubacteria, the tmRNA system frees ribosomes that stall during protein synthesis and adds an ssrA tag to the incompletely translated polypeptide to target it for degradation. The AAA+ ClpXP protease degrades most ssrA-tagged proteins in the Escherichia coli cytoplasm and was recently shown to degrade an ssrA-tagged protein in the inner membrane. However, we find that tmRNA-mediated tagging of E. coli ProW1-182, a different inner-membrane protein, results in degradation by the membrane-tethered AAA+ FtsH protease...
October 11, 2016: Biochemistry
Ekaterina Dzyubak, Mee-Ngan F Yap
Members of the Erm methyltransferase family modify 23S rRNA of the bacterial ribosome and render cross-resistance to macrolides and multiple distantly related antibiotics. Previous studies have shown that the expression of erm is activated when a macrolide-bound ribosome stalls the translation of the leader peptide preceding the co-transcribed erm Ribosome stalling is thought to destabilize the inhibitory stem-loop mRNA structure and exposes the erm Shine-Dalgarno (SD) sequence for translational initiation...
September 19, 2016: Antimicrobial Agents and Chemotherapy
Sara Elgamal, Irina Artsimovitch, Michael Ibba
UNLABELLED: Under conditions of tight coupling between translation and transcription, the ribosome enables synthesis of full-length mRNAs by preventing both formation of intrinsic terminator hairpins and loading of the transcription termination factor Rho. While previous studies have focused on transcription factors, we investigated the role of Escherichia coli elongation factor P (EF-P), an elongation factor required for efficient translation of mRNAs containing consecutive proline codons, in maintaining coupled translation and transcription...
2016: MBio
Peng Liu, Yong Chen, Dan Wang, Yanqiong Tang, Hongqian Tang, Haichao Song, Qun Sun, Yueling Zhang, Zhu Liu
Aeromonas veronii is a pathogenic gram-negative bacterium, which infects a variety of animals and results in mass mortality. The stalled-ribosome rescues are reported to ensure viability and virulence under stress conditions, of which primarily include trans-translation and alternative ribosome-rescue factor A (ArfA) in A. veronii. For identification of specific peptides that interact and inhibit the stalled-ribosome rescues, peptide aptamer library (pTRG-SN-peptides) was constructed using pTRG as vector and Staphylococcus aureus nuclease (SN) as scaffold protein, in which 16 random amino acids were introduced to form an exposed surface loop...
2016: Frontiers in Microbiology
Sascha Lange, W Trent Franks, Nandhakishore Rajagopalan, Kristina Döring, Michel A Geiger, Arne Linden, Barth-Jan van Rossum, Günter Kramer, Bernd Bukau, Hartmut Oschkinat
Proteins are synthesized in cells by ribosomes and, in parallel, prepared for folding or targeting. While ribosomal protein synthesis is progressing, the nascent chain exposes amino-terminal signal sequences or transmembrane domains that mediate interactions with specific interaction partners, such as the signal recognition particle (SRP), the SecA-adenosine triphosphatase, or the trigger factor. These binding events can set the course for folding in the cytoplasm and translocation across or insertion into membranes...
August 2016: Science Advances
Volker M Lauschke, Sabine U Vorrink, Sabrina M L Moro, Fatemah Rezayee, Åsa Nordling, Delilah F G Hendriks, Catherine C Bell, Rowena Sison-Young, B Kevin Park, Christopher E Goldring, Ewa Ellis, Inger Johansson, Souren Mkrtchian, Tommy B Andersson, Magnus Ingelman-Sundberg
: Hepatocytes are dynamic cells that, upon injury, can alternate between nondividing differentiated and dedifferentiated proliferating states in vivo. However, in two-dimensional cultures, primary human hepatocytes (PHHs) rapidly dedifferentiate, resulting in loss of hepatic functions that significantly limits their usefulness as an in vitro model of liver biology, liver diseases, as well as drug metabolism and toxicity. Thus, understanding the underlying mechanisms and stalling of the dedifferentiation process would be highly beneficial to establish more-accurate and relevant long-term in vitro hepatocyte models...
November 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Corey Fyfe, Trudy H Grossman, Kathy Kerstein, Joyce Sutcliffe
Macrolide resistance mechanisms can be target-based with a change in a 23S ribosomal RNA (rRNA) residue or a mutation in ribosomal protein L4 or L22 affecting the ribosome's interaction with the antibiotic. Alternatively, mono- or dimethylation of A2058 in domain V of the 23S rRNA by an acquired rRNA methyltransferase, the product of an erm (erythromycin ribosome methylation) gene, can interfere with antibiotic binding. Acquired genes encoding efflux pumps, most predominantly mef(A) + msr(D) in pneumococci/streptococci and msr(A/B) in staphylococci, also mediate resistance...
October 3, 2016: Cold Spring Harbor Perspectives in Medicine
Vaclav Urban, Jana Dobrovolna, Daniela Hühn, Jana Fryzelkova, Jiri Bartek, Pavel Janscak
Collisions between replication and transcription machineries represent a significant source of genomic instability. RECQ5 DNA helicase binds to RNA-polymerase (RNAP) II during transcription elongation and suppresses transcription-associated genomic instability. Here, we show that RECQ5 also associates with RNAPI and enforces the stability of ribosomal DNA arrays. We demonstrate that RECQ5 associates with transcription complexes in DNA replication foci and counteracts replication fork stalling in RNAPI- and RNAPII-transcribed genes, suggesting that RECQ5 exerts its genome-stabilizing effect by acting at sites of replication-transcription collisions...
August 15, 2016: Journal of Cell Biology
Anaïs M E Cassaignau, Hélène M M Launay, Maria-Evangelia Karyadi, Xiaolin Wang, Christopher A Waudby, Annika Deckert, Amy L Robertson, John Christodoulou, Lisa D Cabrita
During biosynthesis on the ribosome, an elongating nascent polypeptide chain can begin to fold, in a process that is central to all living systems. Detailed structural studies of co-translational protein folding are now beginning to emerge; such studies were previously limited, at least in part, by the inherently dynamic nature of emerging nascent chains, which precluded most structural techniques. NMR spectroscopy is able to provide atomic-resolution information for ribosome-nascent chain complexes (RNCs), but it requires large quantities (≥10 mg) of homogeneous, isotopically labeled RNCs...
August 2016: Nature Protocols
Kwang-Chul Kwon, Hui-Ting Chan, Ileana R León, Rosalind Williams-Carrier, Alice Barkan, Henry Daniell
Codon optimization based on psbA genes from 133 plant species eliminated 105 (human clotting factor VIII heavy chain [FVIII HC]) and 59 (polio VIRAL CAPSID PROTEIN1 [VP1]) rare codons; replacement with only the most highly preferred codons decreased transgene expression (77- to 111-fold) when compared with the codon usage hierarchy of the psbA genes. Targeted proteomic quantification by parallel reaction monitoring analysis showed 4.9- to 7.1-fold or 22.5- to 28.1-fold increase in FVIII or VP1 codon-optimized genes when normalized with stable isotope-labeled standard peptides (or housekeeping protein peptides), but quantitation using western blots showed 6...
September 2016: Plant Physiology
Scot P Ouellette, Kelsey J Rueden, Elizabeth A Rucks
In evolving to an obligate intracellular niche, Chlamydia has streamlined its genome by eliminating superfluous genes as it relies on the host cell for a variety of nutritional needs like amino acids. However, Chlamydia can experience amino acid starvation when the human host cell in which the bacteria reside is exposed to interferon gamma (IFN-γ), which leads to a tryptophan (Trp)-limiting environment via induction of the enzyme indoleamine-2,3-dioxygenase (IDO). The stringent response is used to respond to amino acid starvation in most bacteria but is missing from Chlamydia Thus, how Chlamydia, a Trp auxotroph, responds to Trp starvation in the absence of a stringent response is an intriguing question...
September 2016: Infection and Immunity
Youn Na, Sungjin Park, Changhee Lee, Dong-Kyu Kim, Joo Min Park, Shanthini Sockanathan, Richard L Huganir, Paul F Worley
The immediate early gene Arc (also Arg3.1) produces rapid changes in synaptic properties that are linked to de novo translation. Here we develop a novel translation reporter that exploits the rapid maturation and "flash" kinetics of Gaussia luciferase (Gluc) to visualize Arc translation. Following glutamate stimulation, discrete Arc-Gluc bioluminescent flashes representing sites of de novo translation are detected within 15 s at distributed sites in dendrites, but not spines. Flashes are episodic, lasting ∼20 s, and may be unitary or repeated at ∼minute intervals at the same sites...
August 3, 2016: Neuron
Adélaïde Saint-Léger, Carla Bello, Pablo D Dans, Adrian Gabriel Torres, Eva Maria Novoa, Noelia Camacho, Modesto Orozco, Fyodor A Kondrashov, Lluís Ribas de Pouplana
Understanding the principles that led to the current complexity of the genetic code is a central question in evolution. Expansion of the genetic code required the selection of new transfer RNAs (tRNAs) with specific recognition signals that allowed them to be matured, modified, aminoacylated, and processed by the ribosome without compromising the fidelity or efficiency of protein synthesis. We show that saturation of recognition signals blocks the emergence of new tRNA identities and that the rate of nucleotide substitutions in tRNAs is higher in species with fewer tRNA genes...
April 2016: Science Advances
Selom K Doamekpor, Joong-Won Lee, Nathaniel L Hepowit, Cheng Wu, Clement Charenton, Marilyn Leonard, Mario H Bengtson, Kanagalaghatta R Rajashankar, Matthew S Sachs, Christopher D Lima, Claudio A P Joazeiro
The Ltn1 E3 ligase (listerin in mammals) has emerged as a paradigm for understanding ribosome-associated ubiquitylation. Ltn1 binds to 60S ribosomal subunits to ubiquitylate nascent polypeptides that become stalled during synthesis; among Ltn1's substrates are aberrant products of mRNA lacking stop codons [nonstop translation products (NSPs)]. Here, we report the reconstitution of NSP ubiquitylation in Neurospora crassa cell extracts. Upon translation in vitro, ribosome-stalled NSPs were ubiquitylated in an Ltn1-dependent manner, while still ribosome-associated...
July 19, 2016: Proceedings of the National Academy of Sciences of the United States of America
Aravinth Kumar Jayabalan, Anthony Sanchez, Ra Young Park, Sang Pil Yoon, Gum-Yong Kang, Je-Hyun Baek, Paul Anderson, Younghoon Kee, Takbum Ohn
Stress granules (SGs) harbour translationally stalled messenger ribonucleoproteins and play important roles in regulating gene expression and cell fate. Here we show that neddylation promotes SG assembly in response to arsenite-induced oxidative stress. Inhibition or depletion of key components of the neddylation machinery concomitantly inhibits stress-induced polysome disassembly and SG assembly. Affinity purification and subsequent mass-spectrometric analysis of Nedd8-conjugated proteins from translationally stalled ribosomal fractions identified ribosomal proteins, translation factors and RNA-binding proteins (RBPs), including SRSF3, a previously known SG regulator...
2016: Nature Communications
Stefan Arenz, Lars V Bock, Michael Graf, C Axel Innis, Roland Beckmann, Helmut Grubmüller, Andrea C Vaiana, Daniel N Wilson
Nascent polypeptides can induce ribosome stalling, regulating downstream genes. Stalling of ErmBL peptide translation in the presence of the macrolide antibiotic erythromycin leads to resistance in Streptococcus sanguis. To reveal this stalling mechanism we obtained 3.6-Å-resolution cryo-EM structures of ErmBL-stalled ribosomes with erythromycin. The nascent peptide adopts an unusual conformation with the C-terminal Asp10 side chain in a previously unseen rotated position. Together with molecular dynamics simulations, the structures indicate that peptide-bond formation is inhibited by displacement of the peptidyl-tRNA A76 ribose from its canonical position, and by non-productive interactions of the A-tRNA Lys11 side chain with the A-site crevice...
2016: Nature Communications
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