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Impacts of uORF codon identity and position on translation regulation

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posted on 31.10.2019, 16:37 authored by Yizhu LinYizhu Lin, Gemma MayGemma May, Hunter Kready, Lauren Nazzaro, Mao Mao, Pieter Spealman, Yehuda CreegerYehuda Creeger, C. Joel McManusC. Joel McManus
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.

Funding

National Institutes of Health R01 GM121895

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Publisher Statement

This is the published version of Yizhu Lin, Gemma E May, Hunter Kready, Lauren Nazzaro, Mao Mao, Pieter Spealman, Yehuda Creeger, C Joel McManus, Impacts of uORF codon identity and position on translation regulation, Nucleic Acids Research, Volume 47, Issue 17, 26 September 2019, Pages 9358–9367, https://doi.org/10.1093/nar/gkz681 © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License This article was published open access using the Carnegie Mellon University Libraries' Article Processing Charge (APC) fund.

Date

08/08/2019

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