Impact of the Diversity in the 5' UTR on Translation Regulation

The 5' untranslated region (UTR) of mRNAs is crucial to regulate translation initiation. Diversity in the 5' UTR can be created by alternative transcription start site (TSS) selection and alternative splicing. Alternative TSS directly impact the first exon length or alternative first exon usage, while alternative splicing further contributes to generating different 5' UTR isoforms by for example, cassette exons inclusion, intron retention, and alternative 5' or 3' splice sites. Alternative TSS and alternative splicing in the 5' UTR directly affect translation efficiency by generating different isoforms that may include or exclude regulatory sequence elements and secondary structures in the 5' UTR. Among the regulatory elements, 5' UTRs may harbor translation-inhibitory upstream open reading frames (uORFs) as well as internal ribosome entry sites (IRESs), which are able to recruit the ribosome in a cap-independent manner. Both uORF- and IRES-mediated mechanisms contribute to target-specific protein production, especially under stress conditions associated with an inhibition of global translation. Mechanisms generating different 5' UTR isoforms therefore represent an additional sophisticated layer to regulate transcript-selective translation efficiency.