Key Points
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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.
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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.
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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.
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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.
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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.
Abstract
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 in the 5′ untranslated region (UTR) can impede binding and movement of the 40S ribosome. The canonical eukaryotic translation initiation factor eIF4A (also known as DDX2), together with its accessory proteins eIF4B and eIF4H, is thought to act as a helicase that unwinds secondary structures in the mRNA 5′ UTR. Growing evidence suggests that other helicases are also important for translation initiation and may promote the scanning processivity of the 40S subunit, synergize with eIF4A to 'melt' secondary structures or facilitate translation of a subset of mRNAs.
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Acknowledgements
We apologize to our colleagues whose work was not included in this Review owing to space limitations. We thank C. Lister and P. Kirk for technical support, T. Nevarko and M. Kowanda for assisting with the preparation of the manuscript and T. Alain, N. Liu and G. Hernandez for valuable discussions. A. P. is holder of an award from the Fonds de la Recherche en Santé Québec, Canada. This work was supported by grants from the Canadian Institutes of Health Research and the Canadian Cancer Society to N. S., who is a Howard Hughes Medical Institute International Scholar.
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Glossary
- Shine–Dalgarno sequence
-
A ribosomal binding site of approximately eight nucleotides in the mRNA of bacteria, located upstream of the initiation codon. Helps to recruit the small ribosomal subunit to the mRNA to initiate protein synthesis.
- Initiator tRNA
-
(Met-tRNAMeti). A tRNA, linked with Met through an aminoacyl group, that is used to initiate protein synthesis. Its anticodon is complementary to the AUG initiation codon. Forms a highly specific ternary complex with eukaryotic translation initiation factor 2 and GTP, and binds to the ribosomal P site.
- P site
-
The site on the 40S ribosomal subunit that accommodates Met-tRNAMeti or the tRNA that is linked to the growing peptide chain.
- Translocase
-
An enzyme that couples ATP hydrolysis to directional movement on single- or double-stranded nucleic acids.
- Polysome
-
A cluster of mRNA-bound, elongating 80S ribosomal complexes. Also known as a polyribosome.
- Micro RNA
-
A small RNA of ∼21 nucleotides that binds to argonaute proteins and regulates the expression of a large number of mRNAs, with which it is partially complementary in sequence.
- Chromatoid body
-
A large perinuclear ribonucleoprotein particle of germ cells that might organize and control RNA processing.
- Piwi-interacting RNA
-
A small RNA of ∼30 nucleotides that interacts with argonaute-related piwi proteins. Has been linked to transcriptional gene silencing of retrotransposons and other genetic elements in germ line cells, particularly those involved in spermatogenesis.
- Processing body
-
A distinct cytoplasmic focus in the eukaryotic cell that contains many enzymes involved in mRNA turnover.
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Parsyan, A., Svitkin, Y., Shahbazian, D. et al. mRNA helicases: the tacticians of translational control. Nat Rev Mol Cell Biol 12, 235–245 (2011). https://doi.org/10.1038/nrm3083
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DOI: https://doi.org/10.1038/nrm3083
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