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Dazhi Wang, Lanying Wang, Chunling Ren, Pei Zhang, Mengmeng Wang, Shuyu Zhang
Previously, certain experiments have suggested that density-regulated re-initiation and release factor ( DENR ) could serve important roles in cancer, however, to the best of our knowledge, a comprehensive analysis of DENR and its association with cancer patient survival is lacking. The aim of the current study was to investigate the expression of DENR in multiple tumour types and to evaluate the effects of DENR on survival in malignancies. Sample expression profiles were downloaded from the Gene Expression Omnibus database...
January 2019: Oncology Letters
Ivan B Lomakin, Sergey E Dmitriev, Thomas A Steitz
The density-regulated protein (DENR) and the malignant T cell-amplified sequence 1 (MCT-1/MCTS1) oncoprotein support noncanonical translation initiation, promote translation reinitiation on a specific set of mRNAs with short upstream reading frames, and regulate ribosome recycling. DENR and MCT-1 form a heterodimer, which binds to the ribosome. We determined the crystal structure of the heterodimer formed by human MCT-1 and the N-terminal domain of DENR at 2.0-Å resolution. The structure of the heterodimer reveals atomic details of the mechanism of DENR and MCT-1 interaction...
December 24, 2018: Proceedings of the National Academy of Sciences of the United States of America
David J Young, Desislava S Makeeva, Fan Zhang, Aleksandra S Anisimova, Elena A Stolboushkina, Fardin Ghobakhlou, Ivan N Shatsky, Sergey E Dmitriev, Alan G Hinnebusch, Nicholas R Guydosh
The recycling of ribosomal subunits after translation termination is critical for efficient gene expression. Tma64 (eIF2D), Tma20 (MCT-1), and Tma22 (DENR) function as 40S recycling factors in vitro, but it is unknown whether they perform this function in vivo. Ribosome profiling of tma deletion strains revealed 80S ribosomes queued behind the stop codon, consistent with a block in 40S recycling. We found that unrecycled ribosomes could reinitiate translation at AUG codons in the 3' UTR, as evidenced by peaks in the footprint data and 3' UTR reporter analysis...
September 6, 2018: Molecular Cell
Yasar Luqman Ahmed, Sibylle Schleich, Jonathan Bohlen, Nicolas Mandel, Bernd Simon, Irmgard Sinning, Aurelio A Teleman
The succession of molecular events leading to eukaryotic translation reinitiation-whereby ribosomes terminate translation of a short open reading frame (ORF), resume scanning, and then translate a second ORF on the same mRNA-is not well understood. Density-regulated reinitiation and release factor (DENR) and multiple copies in T-cell lymphoma-1 (MCTS1) are implicated in promoting translation reinitiation both in vitro in translation extracts and in vivo. We present here the crystal structure of MCTS1 bound to a fragment of DENR...
June 2018: PLoS Biology
Christopher U T Hellen
Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide. The post-termination complex is then disassembled, enabling its constituents to participate in further rounds of translation. Ribosome recycling involves splitting of the 80S ribosome by the ATP-binding cassette protein ABCE1 to release the 60S subunit...
October 1, 2018: Cold Spring Harbor Perspectives in Biology
Melanie Weisser, Tanja Schäfer, Marc Leibundgut, Daniel Böhringer, Christopher Herbert Stanley Aylett, Nenad Ban
After having translated short upstream open reading frames, ribosomes can re-initiate translation on the same mRNA. This process, referred to as re-initiation, controls the translation of a large fraction of mammalian cellular mRNAs, many of which are important in cancer. Key ribosomal binding proteins involved in re-initiation are the eukaryotic translation initiation factor 2D (eIF2D) or the homologous complex of MCT-1/DENR. We determined the structures of these factors bound to the human 40S ribosomal subunit in complex with initiator tRNA positioned on an mRNA start codon in the P-site using a combination of cryoelectron microscopy and X-ray crystallography...
August 3, 2017: Molecular Cell
Ivan B Lomakin, Elena A Stolboushkina, Anand T Vaidya, Chenguang Zhao, Maria B Garber, Sergey E Dmitriev, Thomas A Steitz
The repertoire of the density-regulated protein (DENR) and the malignant T cell-amplified sequence 1 (MCT-1/MCTS1) oncoprotein was recently expanded to include translational control of a specific set of cancer-related mRNAs. DENR and MCT-1 form the heterodimer, which binds to the ribosome and operates at both translation initiation and reinitiation steps, though by a mechanism that is yet unclear. Here, we determined the crystal structure of the human small ribosomal subunit in complex with DENR-MCT-1. The structure reveals the location of the DENR-MCT-1 dimer bound to the small ribosomal subunit...
July 18, 2017: Cell Reports
Sibylle Schleich, Julieta M Acevedo, Katharina Clemm von Hohenberg, Aurelio A Teleman
The non-canonical initiation factors DENR and MCTS1 have been linked to cancer and autism. We recently showed in Drosophila that DENR and MCTS1 regulate translation re-initiation on transcripts containing upstream Open Reading Frames (uORFs) with strong Kozak sequences (stuORFs). Due to the medical relevance of DENR and MCTS1, it is worthwhile identifying the transcripts in human cells that depend on DENR and MCTS1 for their translation. We show here that in humans, as in Drosophila, transcripts with short stuORFs require DENR and MCTS1 for their optimal expression...
June 16, 2017: Scientific Reports
Daria A Tsareva, Dmitry I Osolodkin, Dmitry A Shulga, Alexander A Oliferenko, Sergey A Pisarev, Vladimir A Palyulin, Nikolay S Zefirov
Two fast empirical charge models, Kirchhoff Charge Model (KCM) and Dynamic Electronegativity Relaxation (DENR), had been developed in our laboratory previously for widespread use in drug design research. Both models are based on the electronegativity relaxation principle (Adv. Quantum Chem. 2006, 51, 139-156) and parameterized against ab initio dipole/quadrupole moments and molecular electrostatic potentials, respectively. As 3D QSAR studies comprise one of the most important fields of applied molecular modeling, they naturally have become the first topic to test our charges and thus, indirectly, the assumptions laid down to the charge model theories in a case study...
March 14, 2011: Molecular Informatics
Matilda A Haas, Linh Ngo, Shan Shan Li, Sibylle Schleich, Zhengdong Qu, Hannah K Vanyai, Hayley D Cullen, Aida Cardona-Alberich, Ivan E Gladwyn-Ng, Alistair T Pagnamenta, Jenny C Taylor, Helen Stewart, Usha Kini, Kent E Duncan, Aurelio A Teleman, David A Keays, Julian I-T Heng
Disruptions to neuronal mRNA translation are hypothesized to underlie human neurodevelopmental syndromes. Notably, the mRNA translation re-initiation factor DENR is a regulator of eukaryotic translation and cell growth, but its mammalian functions are unknown. Here, we report that Denr influences the migration of murine cerebral cortical neurons in vivo with its binding partner Mcts1, whereas perturbations to Denr impair the long-term positioning, dendritic arborization, and dendritic spine characteristics of postnatal projection neurons...
June 7, 2016: Cell Reports
Katarina Truvé, Peter Dickinson, Anqi Xiong, Daniel York, Kartika Jayashankar, Gerli Pielberg, Michele Koltookian, Eva Murén, Hans-Henrik Fuxelius, Holger Weishaupt, Fredrik J Swartling, Göran Andersson, Åke Hedhammar, Erik Bongcam-Rudloff, Karin Forsberg-Nilsson, Danika Bannasch, Kerstin Lindblad-Toh
Gliomas are the most common form of malignant primary brain tumors in humans and second most common in dogs, occurring with similar frequencies in both species. Dogs are valuable spontaneous models of human complex diseases including cancers and may provide insight into disease susceptibility and oncogenesis. Several brachycephalic breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, but others, including Pug and Pekingese, are not at higher risk. To identify glioma-associated genetic susceptibility factors, an across-breed genome-wide association study (GWAS) was performed on 39 dog glioma cases and 141 controls from 25 dog breeds, identifying a genome-wide significant locus on canine chromosome (CFA) 26 (p = 2...
May 2016: PLoS Genetics
Peggy Janich, Alaaddin Bulak Arpat, Violeta Castelo-Szekely, Maykel Lopes, David Gatfield
Mammalian gene expression displays widespread circadian oscillations. Rhythmic transcription underlies the core clock mechanism, but it cannot explain numerous observations made at the level of protein rhythmicity. We have used ribosome profiling in mouse liver to measure the translation of mRNAs into protein around the clock and at high temporal and nucleotide resolution. We discovered, transcriptome-wide, extensive rhythms in ribosome occupancy and identified a core set of approximately 150 mRNAs subject to particularly robust daily changes in translation efficiency...
December 2015: Genome Research
Sibylle Schleich, Katrin Strassburger, Philipp Christoph Janiesch, Tatyana Koledachkina, Katharine K Miller, Katharina Haneke, Yong-Sheng Cheng, Katrin Kuechler, Georg Stoecklin, Kent E Duncan, Aurelio A Teleman
During cap-dependent eukaryotic translation initiation, ribosomes scan messenger RNA from the 5' end to the first AUG start codon with favourable sequence context. For many mRNAs this AUG belongs to a short upstream open reading frame (uORF), and translation of the main downstream ORF requires re-initiation, an incompletely understood process. Re-initiation is thought to involve the same factors as standard initiation. It is unknown whether any factors specifically affect translation re-initiation without affecting standard cap-dependent translation...
August 14, 2014: Nature
Eytan Zlotorynski
Translation reinitiation of open reading frames (ORFs) located after upstream ORFs is dependent on the DENR–MCT1 complex, which regulates a specific set of mRNAs.
August 2014: Nature Reviews. Molecular Cell Biology
Maxim A Skabkin, Olga V Skabkina, Christopher U T Hellen, Tatyana V Pestova
During ribosome recycling, posttermination complexes are dissociated by ABCE1 and eRF1 into 60S and tRNA/mRNA-associated 40S subunits, after which tRNA and mRNA are released by eIF1/eIF1A, Ligatin, or MCT-1/DENR. Occasionally, 40S subunits remain associated with mRNA and reinitiate at nearby AUGs. We recapitulated reinitiation using a reconstituted mammalian translation system. The presence of eIF2, eIF3, eIF1, eIF1A, and Met-tRNAi(Met) was sufficient for recycled 40S subunits to remain on mRNA, scan bidirectionally, and reinitiate at upstream and downstream AUGs if mRNA regions flanking the stop codon were unstructured...
July 25, 2013: Molecular Cell
Dmitry A Shulga, Dmitry I Osolodkin, Vladimir A Palyulin, Nikolay S Zefirov
Subtle balance of inter- and intramolecular hydrogen bond strength in aqueous solutions often governs the structure and dynamics of molecular species used as potential drugs and in supramolecular applications. In silico molecular dynamics study of water solution of manzamine A has been performed with different atomic charges in order to investigate the influence of charge distribution choice on predicting qualitative and quantitative features of the simulated systems. Various well known charge schemes (MK-ESP, RESP, Mulliken, AMI-BCC, Gasteiger-Hückel, Gasteiger-Marsili, MMFF94, and Dynamic Electronegativity Relaxation - DENR) led to qualitatively different pictures of dynamic behavior of the intramolecular hydrogen bond...
March 2012: Natural Product Communications
Maxim A Skabkin, Olga V Skabkina, Vidya Dhote, Anton A Komar, Christopher U T Hellen, Tatyana V Pestova
Eukaryotic translation initiation begins with ribosomal recruitment of aminoacylated initiator tRNA (Met-tRNA(Met)(i)) by eukaryotic initiation factor eIF2. In cooperation with eIF3, eIF1, and eIF1A, Met-tRNA(Met)(i)/eIF2/GTP binds to 40S subunits yielding 43S preinitiation complexes that attach to the 5'-terminal region of mRNAs and then scan to the initiation codon to form 48S initiation complexes with established codon-anticodon base-pairing. Stress-activated phosphorylation of eIF2alpha reduces the level of active eIF2, globally inhibiting translation...
August 15, 2010: Genes & Development
H G D Dumalagan, A C Gonzales, A V Hallare
Mussels, Perna viridis L., obtained from three selected seafood markets in Metro Manila, were tested for metal content including cadmium, copper, lead, and zinc through atomic absorption spectrophotometry. Water samples from Bacoor Bay, Cavite, which supplies mussels to the market, were likewise subjected to similar metal analyses. Of the metals analyzed in the soft tissues of mussels, only copper and lead with highest obtained values of 10.4 mg/kg and 2.3 mg/kg, respectively exceeded the PEMSEA guideline for safe human consumption...
April 2010: Bulletin of Environmental Contamination and Toxicology
Krystyna Mazan-Mamczarz, Patrick Hagner, Bojie Dai, Sharon Corl, Zhenqui Liu, Ron B Gartenhaus
The MCT-1 oncogene, highly expressed in a subset of non-Hodgkin's lymphomas interacts with the cap complex through its PUA domain. MCT-1 recruits DENR, a SUI1 motif containing protein that promotes translation initiation of cancer-related mRNAs. We reasoned that a PUA-domain mutant protein would repress MCT-1 function and attenuate the malignant phenotype. Human lymphoma cell lines expressing the PUA-domain mutant protein demonstrated reduced anchorage-independent growth and increased susceptibility to apoptosis...
March 2009: Leukemia Research
Krystyna Mazan-Mamczarz, Ronald B Gartenhaus
BACKGROUND: There is often a poor correlation observed between protein and RNA in eukaryotic systems, supporting the emerging pardigm that many of the abnormalities in a cancer cell's proteome may be achieved by differential recruitment of mRNAs to polysomes referred to as the translational profile. The MCT-1 oncogene product has recently been shown to interact with the cap complex and to modulate the translational profile of cell lines when MCT-1 was highly expressed. The MCT-1 protein modifies mRNA translational profiles through its interaction with DENR/DRP, a protein containing an SUI1 domain involved in recognition of the translation initiation codon...
May 2007: Cancer Genomics & Proteomics
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