10 cis-Regulatory Sequences and trans-Acting Factors in Translational Control

Abstract

All nucleus-encoded eukaryotic mRNAs possess a 5′ cap structure (m⁷GpppN) and, with the exception of the metazoan histone mRNAs, a 3′ poly(A) tail as well. These modifications are added cotranscriptionally in the nucleus (Maniatis and Reed 2002; Proudfoot et al. 2002), and they influence many aspects of mRNA metabolism, including splicing, transport, and stability. The cap structure and the poly(A) tail also promote translation initiation, and, as detailed below, their functions in initiation are frequently the direct or indirect targets of regulatory intervention.

Canonical cap-dependent translation initiation can be divided into four substeps: (1) formation of a 43S preinitiation complex, (2) recruitment of the 43S complex to the 5′ end of the mRNA, (3) scanning of the 5′-untranslated region (UTR) and start codon recognition, and (4) assembly of the 80S ribosome (for a detailed description, see Preiss and Hentze 2003; Sonenberg and Dever 2003; Chapter 4). The interplay between cis-acting elements and trans-acting factors can control mRNA translation at all of these steps.

POINTS OF GLOBAL CONTROL DURING TRANSLATION INITIATION
Although all stages of translation can be the target of regulation, most known control mechanisms affect the initiation stage. A broad distinction can be made between global and mRNA-specific translational control processes (Gebauer and Hentze 2004). mRNA-specific control is usually exerted through regulatory elements in the 5′UTR or 3′UTR of the mRNA (Fig. 1; for a more detailed description, see below). Global control frequently results from changes in the phosphorylation state of initiation factors or the regulators that interact with...