mRNA helicases: the tacticians of translational control
Key Points Helicase activity is required for scanning of the 40S ribosomal subunit, in a 5′ to 3′ direction, on the 5′ untranslated region (UTR) of eukaryotic mRNAs that contain secondary structures. The canonical DEAD-box helicase eukaryotic initiation factor 4A (eIF4A; also known as DDX2) is thoug...
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Veröffentlicht in: | Nature reviews. Molecular cell biology 2011-04, Vol.12 (4), p.235-245 |
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Helicase activity is required for scanning of the 40S ribosomal subunit, in a 5′ to 3′ direction, on the 5′ untranslated region (UTR) of eukaryotic mRNAs that contain secondary structures.
The canonical DEAD-box helicase eukaryotic initiation factor 4A (eIF4A; also known as DDX2) is thought to unwind 5′ UTR secondary structures. The weak helicase activity of eIF4A is enhanced when it is a part of the eIF4F complex, which also contains eIF4G and eIF4E. The activity of eIF4A is also enhanced by its modulatory proteins, eIF4B and eIF4H. Major signalling cascades converge to regulate eIF4A activity, mainly through eIF4B.
Several members of the DEAD- and DEAH-box family of helicases are required for translation initiation and their function is not redundant with that of eIF4A. These helicases include yeast Ded1, which is proposed to be required for translation initiation of mRNAs with long 5′ UTRs, and mammalian DEAH-box 29 (DHX29), which is thought to promote the ability of the 43S complex to overcome RNA secondary structures.
In contrast to other helicases, RNA helicase A (RHA; also known as DHX9) and Vasa (VAS) are target-specific. RHA binds mRNAs that have the post-transcriptional control element (PCE) in their 5′ UTR and unwinds the complex PCE secondary structure. VAS binds mRNAs at the U-rich element of the 3′ UTR and facilitates joining of the 60S ribosome subunit by recruiting eIF5B.
Although the sites and mechanisms of action of these helicases seem to be different, their combined action facilitates the process of translation initiation. It is likely that more helicases will be found to be important for translation initiation and, indeed, other helicases are proposed to function in translation initiation (for example, Dhh1 which is homologous to mammalian RCK, and DDX25), but their roles in this process have yet to be studied.
The initiation of translation in eukaryotes can be impeded by secondary structures in the mRNA upstream of the initiation codon. There is increasing evidence that several helicases act in concert to overcome such structures and to promote processive movement of the 40S ribosome subunit.
The translation initiation step in eukaryotes is highly regulated and rate-limiting. During this process, the 40S ribosomal subunit is usually recruited to the 5′ terminus of the mRNA. It then migrates towards the initiation codon, where it is joined by the 60S ribosomal subunit to form the 80S initiation complex. Secondary structures |
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ISSN: | 1471-0072 1471-0080 |
DOI: | 10.1038/nrm3083 |