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Author = Loughran, Gary;
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Displaying Results 1 - 12 of 12 on page 1 of 1
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AMD1 mRNA employs ribosome stalling as a mechanism for molecular memory formation.
(2018)
Yordanova, Martina M.; Loughran, Gary; Zhdanov, Alexander V.; Mariotti, Marco; Kiniry, ...
AMD1 mRNA employs ribosome stalling as a mechanism for molecular memory formation.
(2018)
Yordanova, Martina M.; Loughran, Gary; Zhdanov, Alexander V.; Mariotti, Marco; Kiniry, Stephen J.; O'Connor, Patrick B. F.; Andreev, Dmitry E.; Tzani, Ioanna; Saffert, Paul; Michel, Audrey M.; Gladyshev, Vadim N.; Papkovsky, Dmitri B.; Atkins, John F.; Baranov, Pavel V.
Abstract:
In addition to acting as template for protein synthesis, messenger RNA (mRNA) often contains sensory sequence elements that regulate this process1,2. Here we report a new mechanism that limits the number of complete protein molecules that can be synthesized from a single mRNA molecule of the human AMD1 gene encoding adenosylmethionine decarboxylase 1 (AdoMetDC). A small proportion of ribosomes translating AMD1 mRNA stochastically read through the stop codon of the main coding region. These readthrough ribosomes then stall close to the next in-frame stop codon, eventually forming a ribosome queue, the length of which is proportional to the number of AdoMetDC molecules that were synthesized from the same AMD1 mRNA. Once the entire spacer region between the two stop codons is filled with queueing ribosomes, the queue impinges upon the main AMD1 coding region halting its translation. Phylogenetic analysis suggests that this mechanism is highly conserved in vertebrates and existed in the...
http://hdl.handle.net/10468/5463
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Avoidance of reporter assay distortions from fused dual reporters
(2017)
Loughran, Gary; Howard, Michael T.; Firth, Andrew E.; Atkins, John F.
Avoidance of reporter assay distortions from fused dual reporters
(2017)
Loughran, Gary; Howard, Michael T.; Firth, Andrew E.; Atkins, John F.
Abstract:
Positioning test sequences between fused reporters permits monitoring of both translation levels and framing, before and after the test sequence. Many studies, including those on recoding such as productive ribosomal frameshifting and stop codon readthrough, use distinguishable luciferases or fluorescent proteins as reporters. Occasional distortions, due to test sequence product interference with the individual reporter activities or stabilities, are here shown to be avoidable by the introduction of tandem StopGo sequences (2A) flanking the test sequence. Using this new vector system (pSGDluc), we provide evidence for the use of a 3' stem-loop stimulator for ACP2 readthrough, but failed to detect the reported VEGFA readthrough.
http://hdl.handle.net/10468/4784
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Evidence of efficient stop codon readthrough in four mammalian genes
(2014)
Loughran, Gary; Chou, Ming-Yuan; Ivanov, Ivaylo P.; Jungreis, Irwin; Kellis, Manolis; K...
Evidence of efficient stop codon readthrough in four mammalian genes
(2014)
Loughran, Gary; Chou, Ming-Yuan; Ivanov, Ivaylo P.; Jungreis, Irwin; Kellis, Manolis; Kiran, Anmol M.; Baranov, Pavel V.; Atkins, John F.
Abstract:
Stop codon readthrough is used extensively by viruses to expand their gene expression. Until recent discoveries in Drosophila, only a very limited number of readthrough cases in chromosomal genes had been reported. Analysis of conserved protein coding signatures that extend beyond annotated stop codons identified potential stop codon readthrough of four mammalian genes. Here we use a modified targeted bioinformatic approach to identify a further three mammalian readthrough candidates. All seven genes were tested experimentally using reporter constructs transfected into HEK-293T cells. Four displayed efficient stop codon readthrough, and these have UGA immediately followed by CUAG. Comparative genomic analysis revealed that in the four readthrough candidates containing UGA-CUAG, this motif is conserved not only in mammals but throughout vertebrates with the first six of the seven nucleotides being universally conserved. The importance of the CUAG motif was confirmed using a systemati...
http://hdl.handle.net/10468/5016
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Insights into the mechanisms of eukaryotic translation gained with ribosome profiling
(2016)
Andreev, Dmitry E.; O'Connor, Patrick B. F.; Loughran, Gary; Dmitriev, Sergey E.; ...
Insights into the mechanisms of eukaryotic translation gained with ribosome profiling
(2016)
Andreev, Dmitry E.; O'Connor, Patrick B. F.; Loughran, Gary; Dmitriev, Sergey E.; Baranov, Pavel V.; Shatsky, Ivan N.
Abstract:
The development of Ribosome Profiling (RiboSeq) has revolutionized functional genomics. RiboSeq is based on capturing and sequencing of the mRNA fragments enclosed within the translating ribosome and it thereby provides a â snapshotâ of ribosome positions at the transcriptome wide level. Although the method is predominantly used for analysis of differential gene expression and discovery of novel translated ORFs, the RiboSeq data can also be a rich source of information about molecular mechanisms of polypeptide synthesis and translational control. This review will focus on how recent findings made with RiboSeq have revealed important details of the molecular mechanisms of translation in eukaryotes. These include mRNA translation sensitivity to drugs affecting translation initiation and elongation, the roles of upstream ORFs in response to stress, the dynamics of elongation and termination as well as details of intrinsic ribosome behavior on the mRNA after translation termination. ...
http://hdl.handle.net/10468/3416
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Multiple RNA structures affect translation initiation and UGA redefinition efficiency during synthesis of selenoprotein P
(2017)
Mariotti, Marco; Shetty, Sumangala; Baird, Lisa; Wu, Sen; Loughran, Gary; Copeland, Pau...
Multiple RNA structures affect translation initiation and UGA redefinition efficiency during synthesis of selenoprotein P
(2017)
Mariotti, Marco; Shetty, Sumangala; Baird, Lisa; Wu, Sen; Loughran, Gary; Copeland, Paul R.; Atkins, John F.; Howard, Michael T.
Abstract:
Gene-specific expansion of the genetic code allows for UGA codons to specify the amino acid selenocysteine (Sec). A striking example of UGA redefinition occurs during translation of the mRNA coding for the selenium transport protein, selenoprotein P (SELENOP), which in vertebrates may contain up to 22 in-frame UGA codons. Sec incorporation at the first and downstream UGA codons occurs with variable efficiencies to control synthesis of full-length and truncated SELENOP isoforms. To address how the Selenop mRNA can direct dynamic codon redefinition in different regions of the same mRNA, we undertook a comprehensive search for phylogenetically conserved RNA structures and examined the function of these structures using cell-based assays, in vitro translation systems, and in vivo ribosome profiling of liver tissue from mice carrying genomic deletions of 3′ UTR selenocysteine-insertion-sequences (SECIS1 and SECIS2). The data support a novel RNA structure near the start codon that impacts...
http://hdl.handle.net/10468/5387
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Processive recoding and metazoan evolution of selenoprotein P: Up to 132 UGAs in molluscs
(2019)
Baclaocos, Janinah; Santesmasses, Didac; Mariotti, Marco; Bierła, Katarzyna; Vetick, Mi...
Processive recoding and metazoan evolution of selenoprotein P: Up to 132 UGAs in molluscs
(2019)
Baclaocos, Janinah; Santesmasses, Didac; Mariotti, Marco; Bierła, Katarzyna; Vetick, Michael B.; Lynch, Sharon; McAllen, Rob; Mackrill, John J.; Loughran, Gary; Guigó, Roderic; Szpunar, Joanna; Copeland, Paul R.; Gladyshev, Vadim N.; Atkins, John F.
Abstract:
Selenoproteins typically contain a single selenocysteine, the 21st amino acid, encoded by a context-redefined UGA. However, human selenoprotein P (SelenoP) has a redox-functioning selenocysteine in its N-terminal domain and nine selenium transporter-functioning selenocysteines in its C-terminal domain. Here we show that diverse SelenoP genes are present across metazoa with highly variable numbers of Sec-UGAs, ranging from a single UGA in certain insects, to 9 in common spider, and up to 132 in bivalve molluscs. SelenoP genes were shaped by a dynamic evolutionary process linked to selenium usage. Gene evolution featured modular expansions of an ancestral multi-Sec domain, which led to particularly Sec-rich SelenoP proteins in many aquatic organisms. We focused on molluscs, and chose Pacific oyster Magallana gigas as experimental model. We show that oyster SelenoP mRNA with 46 UGAs is translated full-length in vivo. Ribosome profiling indicates that selenocysteine specification occurs...
http://hdl.handle.net/10468/8769
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Ribosomal frameshifting and transcriptional slippage: from genetic steganography and cryptography to adventitious use
(2016)
Atkins, John F.; Loughran, Gary; Bhatt, Pramod R.; Firth, Andrew E.; Baranov, Pavel V.
Ribosomal frameshifting and transcriptional slippage: from genetic steganography and cryptography to adventitious use
(2016)
Atkins, John F.; Loughran, Gary; Bhatt, Pramod R.; Firth, Andrew E.; Baranov, Pavel V.
Abstract:
Genetic decoding is not ‘frozen’ as was earlier thought, but dynamic. One facet of this is frameshifting that often results in synthesis of a C-terminal region encoded by a new frame. Ribosomal frameshifting is utilized for the synthesis of additional products, for regulatory purposes and for translational ‘correction’ of problem or ‘savior’ indels. Utilization for synthesis of additional products occurs prominently in the decoding of mobile chromosomal element and viral genomes. One class of regulatory frameshifting of stable chromosomal genes governs cellular polyamine levels from yeasts to humans. In many cases of productively utilized frameshifting, the proportion of ribosomes that frameshift at a shift-prone site is enhanced by specific nascent peptide or mRNA context features. Such mRNA signals, which can be 5′ or 3′ of the shift site or both, can act by pairing with ribosomal RNA or as stem loops or pseudoknots even with one component being 4 kb 3′ from the shift site. Transc...
http://hdl.handle.net/10468/3187
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Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response
(2018)
Loughran, Gary; Jungreis, Irwin; Tzani, Ioanna; Power, Michael; Dmitriev, Ruslan I.; Iv...
Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response
(2018)
Loughran, Gary; Jungreis, Irwin; Tzani, Ioanna; Power, Michael; Dmitriev, Ruslan I.; Ivanov, Ivaylo P.; Kellis, Manolis; Atkins, John F.
Abstract:
Although stop codon readthrough is used extensively by viruses to expand their gene expression, verified instances of mammalian readthrough have only recently been uncovered by systems biology and comparative genomics approaches. Previously our analysis of conserved protein coding signatures that extend beyond annotated stop codons predicted stop codon readthrough of several mammalian genes, all of which have been validated experimentally. Four mRNAs display highly efficient stop codon readthrough, and these mRNAs have a UGA stop codon immediately followed by CUAG (UGA_CUAG) that is conserved throughout vertebrates. Extending on the identification of this readthrough motif, we here investigated stop codon readthrough, using tissue culture reporter assays, for all previously untested human genes containing UGA_CUAG. The readthrough efficiency of the annotated stop codon for the sequence encoding vitamin D receptor (VDR) was 6.7%. It was the highest of those tested but all showed nota...
http://hdl.handle.net/10468/5716
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Stringency of start codon selection modulates autoregulation of translation initiation factor eIF5
(2012)
Loughran, Gary; Sachs, Matthew S.; Atkins, John F.; Ivanov, Ivaylo P.
Stringency of start codon selection modulates autoregulation of translation initiation factor eIF5
(2012)
Loughran, Gary; Sachs, Matthew S.; Atkins, John F.; Ivanov, Ivaylo P.
Abstract:
An AUG in an optimal nucleotide context is the preferred translation initiation site in eukaryotic cells. Interactions among translation initiation factors, including eIF1 and eIF5, govern start codon selection. Experiments described here showed that high intracellular eIF5 levels reduced the stringency of start codon selection in human cells. In contrast, high intracellular eIF1 levels increased stringency. High levels of eIF5 induced translation of inhibitory upstream open reading frames (uORFs) in eIF5 mRNA that initiate with AUG codons in conserved poor contexts. This resulted in reduced translation from the downstream eIF5 start codon, indicating that eIF5 autoregulates its own synthesis. As with eIF1, which is also autoregulated through translation initiation, features contributing to eIF5 autoregulation show deep evolutionary conservation. The results obtained provide the basis for a model in which auto- and cross-regulation of eIF5 and eIF1 translation establish a regulatory...
http://hdl.handle.net/10468/5022
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Systematic analysis of the PTEN 5' leader identifies a major AUU initiated proteoform
(2016)
Tzani, Ioanna; Ivanov, Ivaylo P.; Andreev, Dmitry E.; Dmitriev, Ruslan I.; Dean, Kellie...
Systematic analysis of the PTEN 5' leader identifies a major AUU initiated proteoform
(2016)
Tzani, Ioanna; Ivanov, Ivaylo P.; Andreev, Dmitry E.; Dmitriev, Ruslan I.; Dean, Kellie A.; Baranov, Pavel V.; Atkins, John F.; Loughran, Gary
Abstract:
Abundant evidence for translation within the 5′ leaders of many human genes is rapidly emerging, especially, because of the advent of ribosome profiling. In most cases, it is believed that the act of translation rather than the encoded peptide is important. However, the wealth of available sequencing data in recent years allows phylogenetic detection of sequences within 5′ leaders that have emerged under coding constraint and therefore allow for the prediction of functional 5′ leader translation. Using this approach, we previously predicted a CUG-initiated, 173 amino acid N-terminal extension to the human tumour suppressor PTEN. Here, a systematic experimental analysis of translation events in the PTEN 5′ leader identifies at least two additional non-AUG-initiated PTEN proteoforms that are expressed in most human cell lines tested. The most abundant extended PTEN proteoform initiates at a conserved AUU codon and extends the canonical AUG-initiated PTEN by 146 amino acids. All N-term...
http://hdl.handle.net/10468/5715
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TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response
(2018)
Andreev, Dmitry E.; Arnold, Maxim; Kiniry, Stephen J.; Loughran, Gary; Michel, Audrey M...
TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response
(2018)
Andreev, Dmitry E.; Arnold, Maxim; Kiniry, Stephen J.; Loughran, Gary; Michel, Audrey M.; Rachinskii, Dmitrii; Baranov, Pavel V.
Abstract:
Translation initiation is the rate-limiting step of protein synthesis that is downregulated during the Integrated Stress Response (ISR). Previously, we demonstrated that most human mRNAs that are resistant to this inhibition possess translated upstream open reading frames (uORFs), and that in some cases a single uORF is sufficient for the resistance. Here we developed a computational model of Initiation Complexes Interference with Elongating Ribosomes (ICIER) to gain insight into the mechanism. We explored the relationship between the flux of scanning ribosomes upstream and downstream of a single uORF depending on uORF features. Paradoxically, our analysis predicts that reducing ribosome flux upstream of certain uORFs increases initiation downstream. The model supports the derepression of downstream translation as a general mechanism of uORF-mediated stress resistance. It predicts that stress resistance can be achieved with long slowly decoded uORFs that do not favor translation rei...
http://hdl.handle.net/10468/6829
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Translational autoregulation of BZW1 and BZW2 expression by modulating the stringency of start codon selection
(2018)
Loughran, Gary; Firth, Andrew E.; Atkins, John F.; Ivanov, Ivaylo P.
Translational autoregulation of BZW1 and BZW2 expression by modulating the stringency of start codon selection
(2018)
Loughran, Gary; Firth, Andrew E.; Atkins, John F.; Ivanov, Ivaylo P.
Abstract:
The efficiency of start codon selection during ribosomal scanning in eukaryotic translation initiation is influenced by the context or flanking nucleotides surrounding the AUG codon. The levels of eukaryotic translation initiation factors 1 (eIF1) and 5 (eIF5) play critical roles in controlling the stringency of translation start site selection. The basic leucine zipper and W2 domain-containing proteins 1 and 2 (BZW1 and BZW2), also known as eIF5-mimic proteins, are paralogous human proteins containing C-terminal HEAT domains that resemble the HEAT domain of eIF5. We show that translation of mRNAs encoding BZW1 and BZW2 homologs in fungi, plants and metazoans is initiated by AUG codons in conserved unfavorable initiation contexts. This conservation is reminiscent of the conserved unfavorable initiation context that enables autoregulation of EIF1. We show that overexpression of BZW1 and BZW2 proteins enhances the stringency of start site selection, and that their poor initiation codo...
http://hdl.handle.net/10468/5719
Displaying Results 1 - 12 of 12 on page 1 of 1
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