ИСТИНА

The main focus of our current studies is mechanism(s) of mRNA recruitment to mammalian ribosomes. We focus on two aspects of this recruitment: large variations in the eIF4E- and cap-dependence of mRNA binding to 40S ribosomes and the problem of cap-independent translation of cellular mRNAs. Both points are very important for understanding of cancer progression and mechanisms of cell survival after drug treatment. The widely adopted hypothesis says that mRNAs with highly structured 5′ UTRs should require more helicase eIF4A and, hence, be more dependent on the cap and eIF4E. As most of oncogenic factors are encoded by such mRNAs, this hypothesis explains why many tumors have elevated concentrations of eIF4E. Comparison of mRNA translation efficiency directed by different capped and uncapped 5′ UTRs in RNA-transfected cells did not support this idea. There is no correlation between the length and degree of the secondary structure of a 5′ UTR and its cap requirement. These data are strongly supported by recent ribosome profiling experiments performed on mTORinhibited cells. Particularly, the most cap-independent mRNA encodes apoptosis scaffold protein Apaf-1, though its 5′ UTR highly structured. Ironically, we did not find any IRESelement within highly structured 5′ UTRs of the Apaf-1 or other mRNAs with a low cap-dependence. Moreover, the Apaf-1 5′ UTR continues to use a rather effective scanning mechanism during apoptosis when eIF4E is sequestered by 4EBP and eIF4G is partially cleaved. These data allow us to think that some cellular mRNAs are capable of cap- and IRESindependent translation initiation provided by Cap-Independent Translation Enhancers (CITEs). They may function in a way similar to CITE-elements found in uncapped mRNAs of some plant viruses. The proposed mechanism was supported by inserting an eIF4G-binding element from a viral IRES into 5′ UTRs of strongly cap-dependent mRNAs. Such insertion dramatically reduced their requirement for the 5′-terminal m7Gcap, though the translation remained dependent on a vacant 5′- end and occurred by a scanning mechanism. These data may substantiate a new paradigm of translational control under stress conditions.