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https://www.readbyqxmd.com/read/28639196/specific-increase-of-protein-levels-by-enhancing-translation-using-antisense-oligonucleotides-targeting-upstream-open-frames
#1
Xue-Hai Liang, Wen Shen, Stanley T Crooke
A number of diseases are caused by low levels of key proteins; therefore, increasing the amount of specific proteins in human bodies is of therapeutic interest. Protein expression is downregulated by some structural or sequence elements present in the 5' UTR of mRNAs, such as upstream open reading frames (uORF). Translation initiation from uORF(s) reduces translation from the downstream primary ORF encoding the main protein product in the same mRNA, leading to a less efficient protein expression. Therefore, it is possible to use antisense oligonucleotides (ASOs) to specifically inhibit translation of the uORF by base-pairing with the uAUG region of the mRNA, redirecting translation machinery to initiate from the primary AUG site...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28637336/identification-of-arabidopsis-thaliana-upstream-open-reading-frames-encoding-peptide-sequences-that-cause-ribosomal-arrest
#2
Noriya Hayashi, Shun Sasaki, Hiro Takahashi, Yui Yamashita, Satoshi Naito, Hitoshi Onouchi
Specific sequences of certain nascent peptides cause programmed ribosomal arrest during mRNA translation to control gene expression. In eukaryotes, most known regulatory arrest peptides are encoded by upstream open reading frames (uORFs) present in the 5΄-untranslated region of mRNAs. However, to date, a limited number of eukaryotic uORFs encoding arrest peptides have been reported. Here, we searched for arrest peptide-encoding uORFs among Arabidopsis thaliana uORFs with evolutionarily conserved peptide sequences...
June 14, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28623304/identification-of-transcripts-with-short-stuorfs-as-targets-for-denr%C3%A2-mcts1-dependent-translation-in-human-cells
#3
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
https://www.readbyqxmd.com/read/28541577/eif1-modulates-the-recognition-of-suboptimal-translation-initiation-sites-and-steers-gene-expression-via-uorfs
#4
Daria Fijalkowska, Steven Verbruggen, Elvis Ndah, Veronique Jonckheere, Gerben Menschaert, Petra Van Damme
Alternative translation initiation mechanisms such as leaky scanning and reinitiation potentiate the polycistronic nature of human transcripts. By allowing for reprogrammed translation, these mechanisms can mediate biological responses to stimuli. We combined proteomics with ribosome profiling and mRNA sequencing to identify the biological targets of translation control triggered by the eukaryotic translation initiation factor 1 (eIF1), a protein implicated in the stringency of start codon selection. We quantified expression changes of over 4000 proteins and 10 000 actively translated transcripts, leading to the identification of 245 transcripts undergoing translational control mediated by upstream open reading frames (uORFs) upon eIF1 deprivation...
May 24, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28514448/uorf-mediated-translation-allows-engineered-plant-disease-resistance-without-fitness-costs
#5
Guoyong Xu, Meng Yuan, Chaoren Ai, Lijing Liu, Edward Zhuang, Sargis Karapetyan, Shiping Wang, Xinnian Dong
Controlling plant disease has been a struggle for humankind since the advent of agriculture. Studies of plant immune mechanisms have led to strategies of engineering resistant crops through ectopic transcription of plants' own defence genes, such as the master immune regulatory gene NPR1 (ref. 1). However, enhanced resistance obtained through such strategies is often associated with substantial penalties to fitness, making the resulting products undesirable for agricultural applications. To remedy this problem, we sought more stringent mechanisms of expressing defence proteins...
May 25, 2017: Nature
https://www.readbyqxmd.com/read/28494858/mtorc1-balances-cellular-amino-acid-supply-with-demand-for-protein-synthesis-through-post-transcriptional-control-of-atf4
#6
Yeonwoo Park, Andrea Reyna-Neyra, Lucas Philippe, Carson C Thoreen
The mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that is commonly deregulated in human diseases. Here we find that mTORC1 controls a transcriptional program encoding amino acid transporters and metabolic enzymes through a mechanism also used to regulate protein synthesis. Bioinformatic analysis of mTORC1-responsive mRNAs identified a promoter element recognized by activating transcription factor 4 (ATF4), a key effector of the integrated stress response. ATF4 translation is normally induced by the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) through a mechanism that requires upstream open reading frames (uORFs) in the ATF4 5' UTR...
May 9, 2017: Cell Reports
https://www.readbyqxmd.com/read/28461717/molecular-cloning-and-characterization-of-s-adenosylmethionine-decarboxylase-gene-in-rubber-tree-hevea-brasiliensis
#7
Manman Zhao, Hui Liu, Zhi Deng, Jiangshu Chen, Hong Yang, Huiping Li, Zhihui Xia, Dejun Li
S-Adenosylmethionine decarboxylase (SAMDC) is a key rate-limiting enzyme involved in polyamines biosynthesis, and it plays important roles in plant growth, development and stresses response. However, no SAMDC gene was reported in rubber tree. Here we report characteristics of an SAMDC gene (HbSAMDC1) in rubber tree. HbSAMDC1 contains a 1080 bp open reading frame (ORF) encoding 359 amino acids. Quantitative real-time PCR analyses revealed that HbSAMDC1 exhibited distinct expression patterns in different tissues and was regulated by various stresses, including drought, cold, salt, wounding, and H2O2 treatments...
April 2017: Physiology and Molecular Biology of Plants: An International Journal of Functional Plant Biology
https://www.readbyqxmd.com/read/28461625/transcript-specific-characteristics-determine-the-contribution-of-endo-and-exonucleolytic-decay-pathways-during-the-degradation-of-nonsense-mediated-decay-substrates
#8
Franziska Ottens, Volker Boehm, Christopher R Sibley, Jernej Ule, Niels H Gehring
Nonsense-mediated mRNA decay (NMD) controls gene expression by eliminating mRNAs with premature or aberrant translation termination. Degradation of NMD substrates is initiated by the central NMD factor UPF1, which recruits the endonuclease SMG6 and the deadenylation-promoting SMG5/7 complex. The extent to which SMG5/7 and SMG6 contribute to the degradation of individual substrates and their regulation by UPF1 remain elusive. Here we map transcriptome-wide sites of SMG6-mediated endocleavage via 3' fragment capture and degradome sequencing...
May 1, 2017: RNA
https://www.readbyqxmd.com/read/28420619/analysis-of-variants-in-upstream-open-reading-frames-of-human-globin-related-genes
#9
Ye Yuhua, Zhang Qianqian, Zhong Jianmei, Li Yihong, Zhang Li, Yu Qiuxia, Xu Xiangmin
β-thalassemia is an autosomal recessive monogenic disease that is caused by defects in the production of β-like globin chains. Activation of γ-globin gene and the increase in fetal hemoglobin expression have been demonstrated as one of the most important factors to ameliorate the clinical outcome of β-thalassemia patients. In this study, 202 genes or miRNAs associated with human hemoglobin gene expression from 1802 β-thalassemia patients were analyzed with target capture and next generation sequencing strategies in terms of functional variants that might affect hemoglobin gene expression...
March 20, 2017: Yi Chuan, Hereditas
https://www.readbyqxmd.com/read/28414973/regulation-of-antibiotic-resistance-by-non-coding-rnas-in-bacteria
#10
REVIEW
Daniel Dar, Rotem Sorek
Antibiotic resistance genes are commonly regulated by sophisticated mechanisms that activate gene expression in response to antibiotic exposure. Growing evidence suggest that cis-acting non-coding RNAs play a major role in regulating the expression of many resistance genes, specifically those which counteract the effects of translation-inhibiting antibiotics. These ncRNAs reside in the 5'UTR of the regulated gene, and sense the presence of the antibiotics by recruiting translating ribosomes onto short upstream open reading frames (uORFs) embedded in the ncRNA...
April 14, 2017: Current Opinion in Microbiology
https://www.readbyqxmd.com/read/28368337/crispr-cas9-mediated-gene-silencing-of-the-mutant-huntingtin-gene-in-an-in-vitro-model-of-huntington-s-disease
#11
Nivya Kolli, Ming Lu, Panchanan Maiti, Julien Rossignol, Gray L Dunbar
Huntington's disease (HD) is a fatal neurodegenerative genetic disease characterized by a loss of neurons in the striatum. It is caused by a mutation in the Huntingtin gene (HTT) that codes for the protein huntingtin (HTT). The mutant Huntingtin gene (mHTT) contains extra poly-glutamine (CAG) repeats from which the translated mutant huntingtin proteins (mHTT) undergo inappropriate post-translational modifications, conferring a toxic gain of function, in addition to its non-functional property. In order to curb the production of the mHTT, we have constructed two CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9 (CRISPR associate protein) plasmids, among which one nicks the DNA at untranslated region upstream to the open reading frame (uORF), and the other nicks the DNA at exon1-intron boundary...
April 2, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28366877/translational-effects-and-coding-potential-of-an-upstream-open-reading-frame-associated-with-dopa-responsive-dystonia
#12
Lataisia Jones, Lacy Goode, Eduardo Davila, Amber Brown, Deirdre M McCarthy, Nutan Sharma, Pradeep G Bhide, Ioanna A Armata
Upstream open reading frames (uORFs) have emerged as major post-transcriptional regulatory elements in eukaryotic species. In general, uORFs are initiated by a translation start codon within the 5' untranslated region of a gene (upstream ATG; uATG), and they are negatively correlated with translational efficiency. In addition to their translational regulatory role, some uORFs can code for biologically active short peptides. The importance of uATGs/uORFs is further underscored by human diseases associated with single nucleotide polymorphisms (SNPs), which disrupt existing uORFs or introduce novel uORFs...
March 31, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28343578/untranslated-regions-utrs-orchestrate-translation-reprogramming-in-cellular-stress-responses
#13
REVIEW
Basavaraj Sajjanar, Rajib Deb, Susheel Kumar Raina, Sachin Pawar, Manoj P Brahmane, Avinash V Nirmale, Nitin P Kurade, Gundallahalli B Manjunathareddy, Santanu Kumar Bal, Narendra Pratap Singh
Stress is the result of an organism's interaction with environmental challenges. Regulations of gene expression including translation modulations are critical for adaptation and survival under stress. Untranslated regions (UTRs) of the transcripts play significant roles in translation regulation and continue to raise many intriguing questions in our understanding of cellular stress physiology. IRES (Internal ribosome entry site) and uORF (upstream open reading frame) mediated alternative translation initiations are emerging as unique mechanisms...
April 2017: Journal of Thermal Biology
https://www.readbyqxmd.com/read/28279185/constitutively-stressed-yeast-strains-are-high-yielding-for-recombinant-fps1-implications-for-the-translational-regulation-of-an-aquaporin
#14
Stephanie P Cartwright, Richard A J Darby, Debasmita Sarkar, Nicklas Bonander, Stephane R Gross, Mark P Ashe, Roslyn M Bill
BACKGROUND: We previously selected four strains of Saccharomyces cerevisiae for their ability to produce the aquaporin Fps1 in sufficient yield for further study. Yields from the yeast strains spt3Δ, srb5Δ, gcn5Δ and yTHCBMS1 (supplemented with 0.5 μg/mL doxycycline) that had been transformed with an expression plasmid containing 249 base pairs of 5' untranslated region (UTR) in addition to the primary FPS1 open reading frame (ORF) were 10-80 times higher than yields from wild-type cells expressing the same plasmid...
March 9, 2017: Microbial Cell Factories
https://www.readbyqxmd.com/read/28260789/hbz-mediated-shift-of-jund-from-growth-suppressor-to-tumor-promoter-in-leukemic-cells-by-inhibition-of-ribosomal-protein-s25-expression
#15
M Terol, H Gazon, I Lemasson, M Duc-Dodon, B Barbeau, R Césaire, J-M Mesnard, J-M Péloponèse
Human T-cell leukemia virus type 1 (HTLV-1) basic-leucine zipper (bZIP) factor (HBZ) is a key player in proliferation and transformation of HTLV-1-infected cells, thus contributing to adult T-cell leukemia (ATL) development. HBZ deregulates gene expression within the host cell by interacting with several cellular partners. Through its C-terminal ZIP domain, HBZ is able to contact and activate JunD, a transcription factor of the AP-1 family. JunD mRNA is intronless but can generate two protein isoforms by alternative translation initiation: JunD full-length and Δ JunD, an N-terminal truncated form unresponsive to the tumor suppressor menin...
March 24, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28260621/differential-regulation-of-hepatitis-b-virus-core-protein-expression-and-genome-replication-by-a-small-upstream-open-reading-frame-and-naturally-occurring-mutations-in-the-precore-region
#16
Li Zong, Yanli Qin, Haodi Jia, Lei Ye, Yongxiang Wang, Jiming Zhang, Jack R Wands, Shuping Tong, Jisu Li
Hepatitis B virus (HBV) transcribes two subsets of 3.5-kb RNAs: precore RNA for hepatitis B e antigen (HBeAg) expression, and pregenomic RNA for core and P protein translation as well as genome replication. HBeAg expression could be prevented by mutations in the precore region, while an upstream open reading frame (uORF) has been proposed as a negative regulator of core protein translation. We employed replication competent HBV DNA constructs and transient transfection experiments in Huh7 cells to verify the uORF effect and to explore the alternative function of precore RNA...
May 2017: Virology
https://www.readbyqxmd.com/read/28246118/gtpase-rop2-binds-and-promotes-activation-of-target-of-rapamycin-tor-in-response-to-auxin
#17
Mikhail Schepetilnikov, Joelle Makarian, Ola Srour, Angèle Geldreich, Zhenbiao Yang, Johana Chicher, Philippe Hammann, Lyubov A Ryabova
Target of rapamycin (TOR) promotes reinitiation at upstream ORFs (uORFs) in genes that play important roles in stem cell regulation and organogenesis in plants. Here, we report that the small GTPase ROP2, if activated by the phytohormone auxin, promotes activation of TOR, and thus translation reinitiation of uORF-containing mRNAs. Plants with high levels of active ROP2, including those expressing constitutively active ROP2 (CA-ROP2), contain high levels of active TOR ROP2 physically interacts with and, when GTP-bound, activates TOR in vitro TOR activation in response to auxin is abolished in ROP-deficient rop2 rop6 ROP4 RNAi plants...
April 3, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28198412/a-screening-strategy-for-the-discovery-of-drugs-that-reduce-c-ebp%C3%AE-lip-translation-with-potential-calorie-restriction-mimetic-properties
#18
Mohamad A Zaini, Christine Müller, Tobias Ackermann, Jeanette Reinshagen, Gertrud Kortman, Ole Pless, Cornelis F Calkhoven
An important part of the beneficial effects of calorie restriction (CR) on healthspan and lifespan is mediated through regulation of protein synthesis that is under control of the mechanistic target of rapamycin complex 1 (mTORC1). As one of its activities, mTORC1 stimulates translation into the metabolic transcription factor CCAAT/Enhancer Binding Protein β (C/EBPβ) isoform Liver-specific Inhibitory Protein (LIP). Regulation of LIP expression strictly depends on a translation re-initiation event that requires a conserved cis-regulatory upstream open reading frame (uORF) in the C/EBPβ-mRNA...
February 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28195124/pervasive-translational-regulation-of-the-cell-signalling-circuitry-underlies-mammalian-development
#19
Kotaro Fujii, Zhen Shi, Olena Zhulyn, Nicolas Denans, Maria Barna
The degree and dynamics of translational control during mammalian development remain poorly understood. Here we monitored translation of the mammalian genome as cells become specified and organize into tissues in vivo. This identified unexpected and pervasive translational regulation of most of the core signalling circuitry including Shh, Wnt, Hippo, PI3K and MAPK pathways. We further identify and functionally characterize a complex landscape of upstream open reading frames (uORFs) across 5'-untranslated regions (UTRs) of key signalling components...
February 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/28158752/hnrnps-and-elavl1-cooperate-with-uorfs-to-inhibit-protein-translation
#20
Jiewen Zhang, Lijuan Kong, Sichao Guo, Mengmeng Bu, Qian Guo, Yuan Xiong, Ning Zhu, Chuan Qiu, Xuejing Yan, Qian Chen, Hongfei Zhang, Junling Zhuang, Qiong Wang, Samuel S Zhang, Yan Shen, Meihong Chen
No abstract text is available yet for this article.
October 25, 2016: Nucleic Acids Research
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