Abstract
Translation of cellular RNA to protein is an energy-intensive process through which synthesized proteins dictate cellular processes and function. Translation is regulated in response to extracellular effectors and availability of amino acids intracellularly. Most eukaryotic mRNA rely on the methyl 7-guanosine (m7G) nucleotide cap to recruit the translation machinery, and the uncoupling of translational control that occurs in tumorigenesis plays a significant role in cancer treatment response. This article provides an overview of the mammalian translation initiation process and the primary mechanisms by which it is regulated. An outline of how deregulation of initiation supports tumorigenesis and how initiation at a downstream open reading frame (ORF) of Tousled-like kinase 1 (TLK1) leads to treatment resistance is discussed.
Highlights
The process of translation initiation begins with the formation of two protein complexes that occur in parallel and converge at the 5′ end of the mRNA
Through interaction with eIF4E and the poly A binding protein (PABP), eIF4G bridges the 3′ and 5′ ends of the mRNA forming a closed-loop conformation that aids in spatially localizing the translation machinery for subsequent rounds of protein synthesis on the same translated mRNA [1] (Figure 1)
The alternate initiation factor eIF2A competes with eukaryotic translation initiation factor 2 (eIF2) for loading of initiator tRNA on the 40S complex. eIF2 is the predominant player in translation initiation, but following its phosphorylation and sequestration, contribution of eIF2A to ternary complex formation increases significantly as it is refractory to eIF2 inhibitory kinases [8, 9]
Summary
The process of translation initiation begins with the formation of two protein complexes that occur in parallel and converge at the 5′ end of the mRNA. Sequestration of eIF2B by phospho-eIF2 leads to limited Met-tRNA-engaged PIC and the overriding of initiation at upstream ORFs. Through association of the scanning ribosomal 40S subunit with the ternary complex downstream initiates translation at the ORF.
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