Translational Regulation by eIFs and RNA Modifications in Cancer

Abstract

Translation is a fundamental process in all living organisms that involves the decoding of genetic information in mRNA by ribosomes and translation factors. The dysregulation of mRNA translation is a common feature of tumorigenesis. Protein expression reflects the total outcome of multiple regulatory mechanisms that change the metabolism of mRNA pathways from synthesis to degradation. Accumulated evidence has clarified the role of an increasing amount of mRNA modifications at each phase of the pathway, resulting in translational output. Translation machinery is directly affected by mRNA modifications, influencing translation initiation, elongation, and termination or altering mRNA abundance and subcellular localization. In this review, we focus on the translation initiation factors associated with cancer as well as several important RNA modifications, for which we describe their association with cancer.

Keywords: 2′-O-dimethyladenosine (m6Am); 5-methylcytosine (m5C); N4-acetylcytidine (ac4C); N6; N6-methyladenosine (m6A); RNA modification; pseudouridine (Ψ); translation initiation factor; tumor.

Figure 1

Functions of eIFs and RNA modifications in tumors. Diagram showing the functions of eIFs and m⁶A, m⁶Am, m⁵C, Ψ, and ac⁴C in RNA modification. A variety of eIFs constitute translation initiation complexes that regulate RNA modification and cellular protein translation, directly or indirectly; they interact with one another to regulate the occurrence, development, and biological behavior of tumors.

Figure 2

Overview of eukaryotic translation initiation. Translation is an iterative process. The typical mechanism for the regulation of translation occurs at the rate-limiting stage of initiation, starting with the formation of the EIF2/GTP/Met-tRNA_i^Met TC and involving the control of the functional 40S subunit and its related factors (the 43S preinitiation complex (43S PIC)) assembly. The 43S PIC is a large complex formed by the binding of the 40S ribosomal subunit to the eukaryotic translation initiation factors eIF1, eIF1A, eIF3, and eIF5 and the TC. The recruitment of the 43S PIC to the mRNA template is facilitated by eIF4F, a complex consisting of the mRNA 5′-cap-binding subunit (eIF4E), a large scaffold protein (eIF4G), and an RNA helicase (eIF4A), resulting in the 48S PIC form. eIF4F recruits ribosomes to mRNA through the eIF4E-mRNA cap and eIF4G-eIF3 interaction to form the 48S initiation complex. eIF4G also interacts with poly(A)-binding protein (PABP), which binds to the mRNA 3′ poly(A) tail, resulting in mRNA circularization to stabilize mRNA and facilitate translation. The eIF4A helicase, which unfolds structures near the mRNA 5′-cap with other stronger helicases (DHX29), is involved in the initial interaction of eIF4F with the 5′ end of mRNA and can also facilitate the scanning of the 40S ribosomal subunit towards the start codon by resolving secondary structures in the 5′ untranslated region (UTR). The recognition of the initiation codon by the 43S PIC results in the release of eIF and the joining of the 60S subunit. The formation of the translationally competent 80S ribosome marks the end of initiation and the beginning of elongation.

Figure 3

The molecular composition of RNA modifications. (A) The m⁶A modification of RNA is mediated by proteins called “writes” and “erases”; (B) The m⁶Am modification of RNA is mediated by proteins called “writes” and “erases”; (C) The m⁵C modification of RNA is mediated by proteins called “writes” and “erases”; (D) The ac⁴C modification of RNA is mediated by proteins called “writes” and “erases”; (E) The Ψ modification of RNA is mediated by proteins called “writes” and “erases”. Under the catalysis of the corresponding enzymes, the molecular structure and the enrichment level of RNA are changed to play different biological roles.