1. The Untranslated Regions of mRNAs in Cancer
Samantha L. Schuster, Andrew C. Hsieh 
Trends in Cancer 
Volume 5, Issue 4, Pages (April 2019)
DOI: /j.trecan
Copyright © 2019 Elsevier Inc. Terms and Conditions

2. Figure 1
Key Figure: 5′- and 3′-Untranslated Region (UTR) Elements and How They Are Co-opted in Cancer
(A) The 5′ and 3′UTRs contain many regulatory elements. We show a theoretical mRNA schematic highlighting a few salient examples that have implications in cancer: upstream open reading frames (uORFs), internal ribosome entry sites (IRESs), poly(A) signals (PASs), microRNA (miRNA) binding sites, and several sequence- and structure-based motifs (in green). Throughout the figure, known examples of genes deregulated by each regulatory element in cancer are shown in gold boxes. Known mutations of regulatory elements in cancer are indicated with stars. (B) Under normal conditions: (i) uORFs in the 5′UTR repress translation of the main downstream ORF through preinitiation complex (PIC) blockage or stalling, nonsense-mediated decay (NMD), or PIC disassembly after translation of the uORF; (ii) Under stress, where the translation machinery is downregulated, the PIC more often reads through the uORF and thus translates the downstream ORF more efficiently. (C) IRESs are large structural elements in the 5′UTR that can, through the binding of IRES trans-acting factors (ITAFs), recruit the 40S to the start codon independent of the 5′ cap. (D) Many genes contain multiple PASs in their 3′UTRs that can give rise to differentially cleaved and polyadenylated transcripts. This results in the inclusion or exclusion of other, often destabilizing, cis-elements, affecting downstream gene expression. Often, the use of proximal PASs increases gene expression, whereas distal PASs decrease gene expression. (E) miRNAs are small RNAs that integrate with the RNA-induced silencing complex (RISC) to mediate translational repression and/or mRNA decay of specific transcripts by binding to target sequences, mostly in the 3′UTR. Abbreviations: ARE, AU-rich element; BAT, TGF-β-activated translational element; GRE, G-rich element; MGMT, O6-methylguanine-DNA-methyltransferase; PRTE, pyrimidine-rich translational element; PUF, Pumilio/fem-3 mRNA binding factor; RISC, RNA-induced silencing complex.
Trends in Cancer 2019 5, DOI: ( /j.trecan )
Copyright © 2019 Elsevier Inc. Terms and Conditions

3. Figure 2
Simplified Schematic of mRNA Processing and Canonical Cap-Dependent Translation. (A) Polyadenylation occurs cotranscriptionally in a two-step process of cleavage and adenylation. The polyadenylation signal consists of several upstream and downstream sequence motifs which are recognized by the CPSF (cleavage and polyadenylation specificity factor), CFI (cleavage factor Im), and CstF (cleavage stimulation factor) complexes. (B) Cap-dependent translation begins with the formation of the 43S preinitiation complex (PIC) from the eukaryotic initiation factors eIF1, eIF1A, eIF3, eIF5, ternary complex (eIF2:GTP with meti-tRNA), and the 40S small ribosomal subunit. The cap-binding eIF4F complex, consisting of eIF4E, eIF4G, and eIF4A, recruits the 43S PIC to the cap. The PIC then scans down the 5′UTR until recognition of a start codon. At the start codon, the 60S large ribosomal subunit joins and eIF2:GTP is hydrolyzed to eIF2:GDP. This must be recycled for subsequent rounds of initiation by the guanine exchange factor (GEF) eIF2B. Phosphorylation (P) of the eIF2α subunit inhibits this GEF activity and therefore decreases the availability of the ternary complex and global translation levels. Abbreviations: ORF, open-reading frame; PABP, poly(A)-binding protein.
Trends in Cancer 2019 5, DOI: ( /j.trecan )
Copyright © 2019 Elsevier Inc. Terms and Conditions