Faculty Opinions recommendation of Translational control via protein-regulated upstream open reading frames.

Ribosome-footprint profiling provides genome-wide snapshots of translation, but technical challenges can confound its analysis. Here, we use improved methods to obtain ribosome-footprint profiles and mRNA abundances that more faithfully reflect gene expression in Saccharomyces cerevisiae. Our results support proposals that both the beginning of coding regions and codons matching rare tRNAs are more slowly translated. They also indicate that emergent polypeptides with as few as three basic residues within a 10-residue window tend to slow translation. With the improved mRNA measurements, the variation attributable to translational control in exponentially growing yeast was less than previously reported, and most of this variation could be predicted with a simple model that considered mRNA abundance, upstream open reading frames, cap-proximal structure and nucleotide composition, and lengths of the coding and 5′- untranslated regions. Collectively, our results reveal key features of translational control in yeast and provide a framework for executing and interpreting ribosome- profiling studies.

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The first and fourth upstream open reading frames in GCN4 mRNA have similar initiation efficiencies but respond differently in translational control to change in length and sequence

Molecular and Cellular Biology ◽

10.1128/mcb.8.12.5439-5447.1988 ◽

1988 ◽

Vol 8 (12) ◽

pp. 5439-5447

Author(s):

P P Mueller ◽

B M Jackson ◽

P F Miller ◽

A G Hinnebusch

Keyword(s):

Translational Control ◽

Normal Growth ◽

Open Reading Frames ◽

Regulatory Function ◽

Coding Sequences ◽

Lacz Fusions ◽

Upstream Open Reading Frames ◽

Reading Frames ◽

Starvation Conditions

The third and fourth AUG codons in GCN4 mRNA efficiently repress translation of the GCN4-coding sequences under normal growth conditions. The first AUG codon is approximately 30-fold less inhibitory and is required under amino acid starvation conditions to override the repressing effects of AUG codons 3 and 4. lacZ fusions constructed to functional, elongated versions of the first and fourth upstream open reading frames (URFs) were used to show that AUG codons 1 and 4 function similarly as efficient translational start sites in vivo, raising the possibility that steps following initiation distinguish the regulatory properties of URFs 1 and 4. In accord with this idea, we observed different consequences of changing the length and termination site of URF1 versus changing those of URFs 3 and 4. The latter were lengthened considerably, with little or no effect on regulation. In fact, the function of URFs 3 and 4 was partially reconstituted with a completely heterologous URF. By contrast, certain mutations that lengthen URF1 impaired its positive regulatory function nearly as much as removing its AUG codon did. The same mutations also made URF1 a much more inhibitory element when it was present alone in the mRNA leader. These results strongly suggest that URFs 1 and 4 both function in regulation as translated coding sequences. To account for the phenotypes of the URF1 mutations, we suggest the most ribosomes normally translate URF1 and that the mutations reduce the number of ribosomes that are able to complete URF1 translation and resume scanning downstream. This effect would impair URF1 positive regulatory function if ribosomes must first translate URF1 in order to overcome the strong translational block at the 3'-proximal URFs. Because URF1-lacZ fusions were translated at the same rate under repressing and derepressing conditions, it appears that modulating initiation at URF1 is not the means that is used to restrict the regulatory consequences of URF1 translation to starvation conditions.

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Genome editing of upstream open reading frames enables translational control in plants

Nature Biotechnology ◽

10.1038/nbt.4202 ◽

2018 ◽

Vol 36 (9) ◽

pp. 894-898 ◽

Cited By ~ 65

Author(s):

Huawei Zhang ◽

Xiaomin Si ◽

Xiang Ji ◽

Rong Fan ◽

Jinxing Liu ◽

...

Keyword(s):

Genome Editing ◽

Translational Control ◽

Open Reading Frames ◽

Upstream Open Reading Frames ◽

Reading Frames

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Role of two upstream open reading frames in the translational control of oncogene mdm2

Oncogene ◽

10.1038/sj.onc.1202949 ◽

1999 ◽

Vol 18 (41) ◽

pp. 5631-5637 ◽

Cited By ~ 59

Author(s):

Cheryl Y Brown ◽

Gregory J Mize ◽

Mario Pineda ◽

Donna L George ◽

David R Morris

Keyword(s):

Translational Control ◽

Open Reading Frames ◽

Upstream Open Reading Frames ◽

Reading Frames

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Translational Control of theXenopus laevisConnexin-41 5′-Untranslated Region by Three Upstream Open Reading Frames

Journal of Biological Chemistry ◽

10.1074/jbc.m005531200 ◽

2000 ◽

Vol 275 (40) ◽

pp. 30787-30793 ◽

Cited By ~ 16

Author(s):

Hedda A. Meijer ◽

Wim J. A. G. Dictus ◽

Eelco D. Keuning ◽

Adri A. M. Thomas

Keyword(s):

Translational Control ◽

Untranslated Region ◽

Open Reading Frames ◽

Upstream Open Reading Frames ◽

Reading Frames

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Translational Control of the Transcriptional Activator GCN4 Involves Upstream Open Reading Frames, A General Initiation Factor and a Protein Kinase

Post-Transcriptional Control of Gene Expression ◽

10.1007/978-3-642-75139-4_30 ◽

1990 ◽

pp. 325-335 ◽

Cited By ~ 2

Author(s):

A. G. Hinnebusch ◽

J.-P. Abastado ◽

E. M. Hannig ◽

B. M. Jackson ◽

P. F. Miller ◽

...

Keyword(s):

Protein Kinase ◽

Translational Control ◽

Transcriptional Activator ◽

Open Reading Frames ◽

Initiation Factor ◽

Upstream Open Reading Frames ◽

Reading Frames

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Translational Control of Protein Kinase Cη by Two Upstream Open Reading Frames

Molecular and Cellular Biology ◽

10.1128/mcb.01044-09 ◽

2009 ◽

Vol 29 (22) ◽

pp. 6140-6148 ◽

Cited By ~ 15

Author(s):

Hadas Raveh-Amit ◽

Adva Maissel ◽

Jonathan Poller ◽

Liraz Marom ◽

Orna Elroy-Stein ◽

...

Keyword(s):

Amino Acid ◽

Protein Kinase ◽

Translational Control ◽

Translational Regulation ◽

Normal Growth ◽

Amino Acid Starvation ◽

Open Reading Frames ◽

Pkc Isoforms ◽

Upstream Open Reading Frames ◽

Reading Frames

ABSTRACT Protein kinase C (PKC) represents a family of serine/threonine kinases that play a central role in the regulation of cell growth, differentiation, and transformation. Posttranslational control of the PKC isoforms and their activation have been extensively studied; however, not much is known about their translational regulation. Here we report that the expression of one of the PKC isoforms, PKCη, is regulated at the translational level both under normal growth conditions and during stress imposed by amino acid starvation, the latter causing a marked increase in its protein levels. The 5′ untranslated region (5′ UTR) of PKCη is unusually long and GC rich, characteristic of many oncogenes and growth regulatory genes. We have identified two conserved upstream open reading frames (uORFs) in its 5′ UTR and show their effect in suppressing the expression of PKCη in MCF-7 growing cells. While the two uORFs function as repressive elements that maintain low basal levels of PKCη in growing cells, they are required for its enhanced expression upon amino acid starvation. We show that the translational regulation during stress involves leaky scanning and is dependent on eIF-2α phosphorylation by GCN2. Our work further suggests that translational regulation could provide an additional level for controlling the expression of PKC family members, being more common than currently recognized.

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