17.5.2.Repression via Prevention of Helix Unwinding

Generally, the 5'-UTRs of natural eukaryotic mRNAs are often characterised by a considerable extent of folding, i.e. secondary and, probably, tertiary interactions. RNA helicase activities during initiation of translation contribute to the unwinding (melting) of those structures. The role of repressor proteins can be the recognition and stabilisation of those structures resulting in prevention of translation initiation, first of all by blocking the interaction of the ribosomal 43S initiation complex with the cap-adjacent sequence (Fig. 17.8 A), as in the case of the ferritin mRNA repression (Fig. 17.10). Special stimuli, effectors or environmental conditions should be able to displace a repressor and thus derepress such an mRNA. A mechanism of this kind can be suspected in the cases of ornithine decarboxylase mRNA (Manzella & Blackshear, 1992) and c-myc mRNA (Parkin et al., 1988; Lazarus et al., 1988).

The ornithine decarboxylase (ODC) catalyses the first step in polyamine biosynthesis. The in vivo induction of ODC synthesis at the translational level is observed in response to cell proliferation as well as to the level of polyamines. The 5'-UTR of the ODC mRNA contains a very stable secondary structure (the 5'-proximal long GC-rich hairpin) which is inhibitory for the initiation of translation by itself. Growth stimuli are able to relieve this constitutive translational inhibition, probably via stimulation of the activity of an RNA helicase or relevant initiation factors (eIF4A/eIF4B/eIF4F complex). At the same time a 58 kDa protein has been shown to specifically bind to the hairpin-adjacent region within the 5'-UTR. The protein is absent from tissues with high constitutive synthesis of ODC, and present in tissues where its translation is regulated. From this it can be thought that the 5'-UTR-binding protein is a repressor which prevents the melting of the 5'-proximal stable secondary structure by RNA helicases (initiation factors) in the process of initiation, but dissociates from mRNA under the action of some stimuli, thus permitting melting and initiation. The loss of the affinity of the protein for the 5'-UTR-binding site in response to oxidative conditions has been experimentally demonstrated.

The situation seems to be similar with c-myc mRNA where the 5'-UTR structure is found to be inhibitory for translation. A stable hairpin is present at the beginning of the c-myc mRNA. The inhibition, however, can be observed in some but not all cell lines or translation systems. Moreover, the rate of translation of the c-myc mRNA undergoes dramatic changes depending on the developmental processes of oogenesis and embryogenesis in Xenopus. Two alternatives are possible: (1) either a putative repressor protein that stabilises the 5'-UTR structure and prevents its unwinding is present in different amounts in different cells and regulated during development, or (2) some systems possess more active RNA helicase activities than others and these activities can be changed in developmental processes.

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