Translation regulation plays important roles in both normal physiological conditions and diseases states. This regulation requires cis-regulatory elements located mostly in 5′ and 3′ UTRs and trans-regulatory factors (e.g., RNA binding proteins (RBPs)) which recognize specific RNA features and interact with the translation machinery to modulate its activity. In this paper, we discuss important aspects of 5′ UTR-mediated regulation by providing an overview of the characteristics and the function of the main elements present in this region, like uORF (upstream open reading frame), secondary structures, and RBPs binding motifs and different mechanisms of translation regulation and the impact they have on gene expression and human health when deregulated. 1. Translation Regulation Gene expression can be modulated at multiple levels from chromatin modification to mRNA translation. Despite the importance of transcriptional regulation, it is clear at this point that mRNA levels cannot be used as a sole parameter to justify the protein content of a cell. In fact, in a recent study from our lab, we determined that a direct correlation between mRNA and protein exists for less than a third of analyzed genes in a human cell line. Moreover, our analysis suggested that translation regulation contributes considerably to the protein variation as several parameters related to translation like 5′ UTR, 3′ UTR, coding sequence length, presence of uORFs and amino acid composition, and so forth showed good correlations with the obtained mRNA/protein ratios [1]. Translation regulation functions as an important switch when rapid changes in gene expression are required in reponse to internal and external stimuli (PDGF2, VEGF, TGFβ are examples of genes controlled in such way). Translation regulation also plays a significant role during development and cell differentiation by altering the levels of expression of specific mRNA subsets during a particular time window while the majority of transcripts remain unchanged (reviewed in [2–4]). In this paper, we will focus on the importance of 5′ UTR mediated regulation and the different functional elements present in this region with the exception of IRES which is discussed in a different article of this issue. The main regulatory elements in 5′ UTR are secondary structures (including IRES), binding sites for RNA binding proteins, uAUGs and uORFs (Figure 1). Figure 1: Regulatory elements present in 5′ UTR. 2. 5′ UTR The average length of 5′ UTRs is ~100 to ~220 nucleotides across species [5]. In vertebrates, 5′ UTRs tend to be longer in
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