Impacts of uORF codon identity and position on translation regulation

Nucleic Acids Research
Yizhu LinC Joel McManus

Abstract

Translation regulation plays an important role in eukaryotic gene expression. Upstream open reading frames (uORFs) are potent regulatory elements located in 5' mRNA transcript leaders. Translation of uORFs usually inhibit the translation of downstream main open reading frames, but some enhance expression. While a minority of uORFs encode conserved functional peptides, the coding regions of most uORFs are not conserved. Thus, the importance of uORF coding sequences on their regulatory functions remains largely unknown. We investigated the impact of an uORF coding region on gene regulation by assaying the functions of thousands of variants in the yeast YAP1 uORF. Varying uORF codons resulted in a wide range of functions, including repressing and enhancing expression of the downstream ORF. The presence of rare codons resulted in the most inhibitory YAP1 uORF variants. Inhibitory functions of such uORFs were abrogated by overexpression of complementary tRNA. Finally, regression analysis of our results indicated that both codon identity and position impact uORF function. Our results support a model in which a uORF coding sequence impacts its regulatory functions by altering the speed of uORF translation.

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Citations

Sep 2, 2020·Wiley Interdisciplinary Reviews. RNA·Christina Akirtava, Charles Joel McManus
Sep 3, 2020·International Journal of Molecular Sciences·Ting ZhangYu Zhao
Jun 7, 2020·Biomolecules·Kristen ScopinoMichael P Weir
Sep 19, 2020·PloS One·William A BarrMichael P Weir
Sep 2, 2020·Annual Review of Genetics·Thomas E DeverMatthew S Sachs
Feb 9, 2021·Nucleic Acids Research·Agnes KarasikNicholas R Guydosh
Feb 19, 2021·Nature Communications·Hong ZhangJian Lu
Mar 23, 2021·Nature Communications·David S M LeeYoseph Barash

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Datasets Mentioned

BETA
PRJNA556437

Methods Mentioned

BETA
PCR
Illumina sequencing
DNA-seq
FACS
RNA-seq

Software Mentioned

FACS
BD FacsDiva
uORF
bowtie2
Tecan
FLASh

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