Translational Regulation by Upstream Open Reading Frames and Its Relevance to Human Genetic Disease

Abstract

Upstream open reading frames (uORFs) are cis ‐acting elements, located before or overlapped with the main coding ORF (mORF), that regulate cap‐dependent translation efficiency in a transcript‐specific manner. More than half of the human transcripts bear at least one uORF. In addition, it has been recently revealed that many of these uORFs initiate at non‐AUG codons, which significantly increases the complexity and diversity of the human translatome. These regulons are considered repressors of downstream translation but, in some biological contexts, they induce mORF expression. There are several the mechanisms by which AUG and non‐AUG uORFs regulate gene expression, allowing the cell to control transcript‐specific translation according to its needs. Also, we describe several examples of uORF genetic variants associated with human genetic diseases. Studying these cases and understanding the resultant abnormal mechanisms of uORF‐mediated translational control is of extreme importance for the development of new therapeutic strategies. Key Concepts Upstream open reading frames (uORFs) are cis ‐acting translational regulatory elements present within the 5′ leader sequence of mRNAs. uORFs can regulate gene expression by repressing or promoting translation of the downstream main ORF (mORF), according to the cellular environment. The number of uORFs, the intercistronic distance, the overlap with the mORF and the context of the initiation codon are the uORF‐related structural features that most influence their translational regulatory capacity. uORF‐mediated repression of mORF translation is usually achieved by ribosome dissociation, ribosome stalling, induction of nonsense‐mediated mRNA decay (NMD) or production of inhibitory peptides. uORF‐mediated induction of mORF translation is usually achieved by ribosome bypass or translation reinitiation. uORFs initiated by non‐AUG codons are more frequent than previously appreciated, having important biological functions. uORF‐altering polymorphisms and mutations, which create, disrupt or change a uORF, can cause human genetic diseases. Studying and understanding the uORF‐mediated mechanisms of gene expression regulation may provide knowledge to develop novel therapies for several human diseases.

motifNet: A Neural Network Approach for Learning Functional Sequence Patterns in mRNA

“…6) demonstrate that most of the variants occurring in relative positions with high activation resulted in significant lower translation log fold change. We assumed that the paired motif elements possibly created new upstream open reading frames (uORFs), which are potent regulatory elements located in 5'UTR of mRNA transcript (Fernandes & Romão, 2020;Lin et al, 2019).…”

Translation of ABCE1 Is Tightly Regulated by Upstream Open Reading Frames in Human Colorectal Cells

“…The uORF-encoded peptides can also regulate main ORF expression acting as cis - or trans -repressors [ 18 , 19 , 20 , 21 ]. In the end, the repressive function of uORFs on the main coding sequence translation depends on several factors, such as the number and length of the uORFs, the distance between a uORF and the downstream coding sequence, and the uORF start codon and its context [ 9 , 10 , 13 , 22 , 23 , 24 , 25 ]. Other cis -acting elements can also affect uORF translation efficiency.…”

“…However, not all the uORF-containing transcripts are translationally induced by cellular stress, indicating that uORF-mediated translational regulation is transcript-specific [ 37 ]. Nonetheless, the importance of uORF-mediated translational regulation is well illustrated by the fact that mutations that introduce or disrupt a uORF can cause human disease, including cancer [ 24 , 38 , 39 ]. Thus, identifying when and how uORFs function is essential to understand the etiology of many human diseases.…”