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Mechanisms that mediate translation initiation
- Protein synthesis in eukaryotes: The growing biological relevance of cap-independent translation initiation

Following transcription, processing and nucleo-cytoplasmic export, eukaryotic mRNAs are competent for translation. The regulation of translation rates _ the frequency with which a given mRNA is translated _ plays a critical role in many fundamental biological processes, including cell growth, development and the response to biological cues or environmental stresses (172). Deregulation of translation may also be an important component in the transformation of cells (38, 166). Indeed, modulation of mRNA translation exerts a profound effect on global gene expression (172). In effect, even though two transcripts are present in the cytoplasm in identical quantities, they may be translated at very different rates (172). This phenomenon is due, in part, to the fact that the ribosome does not bind to mRNA directly but must be recruited to the mRNA by the concerted action of a large number of eukaryotic translation initiation factors (eIFs) (78, 222). This recruitment step, also referred to as the initiation phase, can be defined as the process in which a special initiator tRNA, Met-tRNAi, is positioned in the P site of a ribosome located at the correct initiation codon (98). When the initiation stage is complete, the 80S ribosome is capable of dipeptide formation (Fig. 1).

Translation initiation of eukaryotic mRNAs in general occurs by a scanning mechanism. Key features of this model include the recognition of the 5' terminus of the mRNA and its cap structure (m7GpppN), followed by binding of the 40S ribosomal subunit and scanning downstream to the initiation codon (98, 200). A consequence of cap recognition is that eukaryotic mRNAs are monocistronic, since an mRNA contains only a single 5' terminus. On the other hand, cap-dependency allows the cell to control gene expression by modulating the assembly and activity of the cap-binding complex components. Translational control thereby allows the cell to fine-tune gene expression by stimulating or repressing the translation of specific mRNAs, usually through the reversible phosphorylation of translation factors (79, 221). The study of the picornaviruses allowed the characterization of an alternative mechanism of translation initiation. Picornaviruses can initiate translation via an internal ribosome entry segment (IRES), an RNA structure that directly recruits the 40S ribosomal subunits in a cap and 5'-end independent fashion. Therefore, in general and depending on how the 40S ribosomal subunit is recruited to the mRNA, translation initiation can take place by a cap-dependent or a cap-independent fashion.

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