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Limited By:	Author = Ivanov, Ivaylo P.;

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A profusion of upstream open reading frame mechanisms in polyamine-responsive translational regulation (2010)

Ivanov, Ivaylo P.; Atkins, John F.; Michael, Antony J.

A profusion of upstream open reading frame mechanisms in polyamine-responsive translational regulation (2010)

Ivanov, Ivaylo P.; Atkins, John F.; Michael, Antony J.

Abstract:

In many eukaryotic mRNAs one or more short 'upstream' open reading frames, uORFs, precede the initiator of the main coding sequence. Upstream ORFs are functionally diverse as illustrated by their variety of features in polyamine pathway biosynthetic mRNAs. Their propensity to act as sensors for regulatory circuits and to amplify the signals likely explains their occurrence in most polyamine pathway mRNAs. The uORF-mediated polyamine responsive autoregulatory circuits found in polyamine pathway mRNAs exemplify the translationally regulated dynamic interface between components of the proteome and metabolism.

http://hdl.handle.net/10468/5028

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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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Identification of evolutionarily conserved non-AUG-initiated N-terminal extensions in human coding sequences (2011)

Ivanov, Ivaylo P.; Firth, Andrew E.; Michel, Audrey M.; Atkins, John F.; Baranov, Pavel V.

Identification of evolutionarily conserved non-AUG-initiated N-terminal extensions in human coding sequences (2011)

Ivanov, Ivaylo P.; Firth, Andrew E.; Michel, Audrey M.; Atkins, John F.; Baranov, Pavel V.

Abstract:

In eukaryotes, it is generally assumed that translation initiation occurs at the AUG codon closest to the messenger RNA 5' cap. However, in certain cases, initiation can occur at codons differing from AUG by a single nucleotide, especially the codons CUG, UUG, GUG, ACG, AUA and AUU. While non-AUG initiation has been experimentally verified for a handful of human genes, the full extent to which this phenomenon is utilized-both for increased coding capacity and potentially also for novel regulatory mechanisms-remains unclear. To address this issue, and hence to improve the quality of existing coding sequence annotations, we developed a methodology based on phylogenetic analysis of predicted 5' untranslated regions from orthologous genes. We use evolutionary signatures of protein-coding sequences as an indicator of translation initiation upstream of annotated coding sequences. Our search identified novel conserved potential non-AUG-initiated N-terminal extensions in 42 human ...

http://hdl.handle.net/10468/5024

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Ribosomal frameshifting in decoding antizyme mRNAs from yeast and protists to humans: close to 300 cases reveal remarkable diversity despite underlying conservation (2007)

Ivanov, Ivaylo P.; Atkins, John F.

Ribosomal frameshifting in decoding antizyme mRNAs from yeast and protists to humans: close to 300 cases reveal remarkable diversity despite underlying conservation (2007)

Ivanov, Ivaylo P.; Atkins, John F.

Abstract:

The protein antizyme is a negative regulator of intracellular polyamine levels. Ribosomes synthesizing antizyme start in one ORF and at the codon 5' adjacent to its stop codon, shift +1 to a second and partially overlapping ORF which encodes most of the protein. The ribosomal frameshifting is a sensor and effector of an autoregulatory circuit which is conserved in animals, fungi and protists. Stimulatory signals encoded 5' and 3' of the shift site act to program the frameshifting. Despite overall conservation, many individual branches have evolved specific features surrounding the frameshift site. Among these are RNA pseudoknots, RNA stem-loops, conserved primary RNA sequences, nascent peptide sequences and branch-specific 'shifty' codons.

http://hdl.handle.net/10468/5033

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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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Translation initiation from conserved non-AUG codons provides additional layers of regulation and coding capacity (2017)

Ivanov, Ivaylo P.; Wei, Jiajie; Caster, Stephen Z.; Smith, Kristina M.; Michel, Audrey ...

Translation initiation from conserved non-AUG codons provides additional layers of regulation and coding capacity (2017)

Ivanov, Ivaylo P.; Wei, Jiajie; Caster, Stephen Z.; Smith, Kristina M.; Michel, Audrey M.; Zhang, Ying; Firth, Andrew E.; Freitag, Michael; Dunlap, Jay C.; Bell-Pedersen, Deborah; Atkins, John F.; Sachs, Matthew S.

Abstract:

Neurospora crassa cpc-1 and Saccharomyces cerevisiae GCN4 are homologs specifying transcription activators that drive the transcriptional response to amino acid limitation. The cpc-1 mRNA contains two upstream open reading frames (uORFs) in its >700-nucleotide (nt) 5' leader, and its expression is controlled at the level of translation in response to amino acid starvation. We used N. crassa cell extracts and obtained data indicating that cpc-1 uORF1 and uORF2 are functionally analogous to GCN4 uORF1 and uORF4, respectively, in controlling translation. We also found that the 5' region upstream of the main coding sequence of the cpc-1 mRNA extends for more than 700 nucleotides without any in-frame stop codon. For 100 cpc-1 homologs from Pezizomycotina and from selected Basidiomycota, 5' conserved extensions of the CPC1 reading frame are also observed. Multiple non-AUG near-cognate codons (NCCs) in the CPC1 reading frame upstream of uORF2, some deeply conserved, could...

http://hdl.handle.net/10468/4788

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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