Abstract
Short upstream open reading frames (uORFs) are cis-acting elements located within the 5′-leader sequence of transcripts and are defined by an initiation codon in-frame with a termination codon located upstream or downstream of its main ORF (mORF) initiation codon. Recent genome-wide ribosome profiling studies have confirmed the widespread presence of uORFs and have shown that many uORFs can initiate with non-AUG codons. uORFs can impact gene expression of the downstream mORF by triggering mRNA decay or by regulating translation. Thus, disruption or creation of uORFs can elicit the development of several genetic diseases. Here, we review the mechanisms by which AUG- and non-AUG uORFs regulate translation. We also show some examples of uORF deregulation in human genetic diseases, focusing mainly on cancer. The knowledge of how uORF deregulation drives the onset of a disease, points out the need to screen the 5′-leader sequences of the transcripts in search for potential disease-related variants. This information will be relevant for the implementation of new diagnostic and/or therapeutic tools.
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Acknowledgements
Work partially supported by UID/MULTI/04046/2013 centre grant from FCT, Portugal (to BioISI), and by National Institute of Health Dr. Ricardo Jorge. J.F.P.S. is recipient of a fellowship from BioSys PhD programme (SFRH/BD/106081/2015) from FCT (Portugal). R.Q.F. is recipient of a fellowship from BioSys PhD programme (SFRH/BD/114392/2016) from FCT (Portugal).
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Silva, J., Fernandes, R., Romão, L. (2019). Translational Regulation by Upstream Open Reading Frames and Human Diseases. In: Romão, L. (eds) The mRNA Metabolism in Human Disease. Advances in Experimental Medicine and Biology, vol 1157. Springer, Cham. https://doi.org/10.1007/978-3-030-19966-1_5
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