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The DDX5/Dbp2 subfamily of DEAD‐box RNA helicases

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The mammalian DEAD‐box RNA helicase DDX5, its paralog DDX17, and their orthologs in Saccharomyces cerevisiae and Drosophila melanogaster, namely Dbp2 and Rm62, define a subfamily of DEAD‐box proteins. Members from this subfamily share highly conserved protein sequences and cellular functions. They are involved in multiple steps of RNA metabolism including mRNA processing, microRNA processing, ribosome biogenesis, RNA decay, and regulation of long noncoding RNA activities. The DDX5/Dbp2 subfamily is also implicated in transcription regulation, cellular signaling pathways, and energy metabolism. One emerging theme underlying the diverse cellular functions is that the DDX5/Dbp2 subfamily of DEAD‐box helicases act as chaperones for complexes formed by RNA molecules and proteins (RNP) in vivo. This RNP chaperone activity governs the functions of various RNA species through their lifetime. Importantly, mammalian DDX5 and DDX17 are involved in cancer progression when overexpressed through alteration of transcription and signaling pathways, meaning that they are possible targets for cancer therapy. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
DEAD‐box proteins unwind duplexes nonprocessively via local strand separation. Schematic representation of the unwinding cycle of a prototypical DEAD‐box RNA helicase. Lines represent RNA strands and the two ovals represent the two RecA‐like domains that are connected by a flexible linker. In the absence of any nucleotide and RNA, the two RecA‐like domains are farther apart and exhibit a flexible “opened, unproductive” conformation. During unwinding, the two RecA‐like domains come closer together to form a “closed, productive” conformation upon binding to the double‐stranded RNA (dsRNA) and ATP (step 1). Closing of the two domains bends one strand of the dsRNA and results in local duplex destabilization (~6 bp). Duplexes longer than 6 bp require multiple cycles of unwinding. ATP hydrolysis and inorganic phosphate release convert the two RecA‐like domains back to the “opened” conformation (step 2). This causes dissociation of the helicase core from the partially opened dsRNA. The partially opened dsRNA can potentially snap back to produce a nonproductive unwinding cycle (dotted arrow) or is subjected to another round of local duplex destabilization (step 3). Another round of local duplex destabilization happens after the ADP is exchanged to ATP in the DEAD‐box protein or a new ATP‐bound DEAD‐box protein recognizes the partially opened dsRNA. This allows the DEAD‐box protein to fully disrupt the partially opened duplex. Upon ATP hydrolysis, the ADP‐Pi‐bound DEAD‐box protein still associates with the bent strand whereas the nonbent strand is released (step 4). The bent strand is eventually dissociated from the DEAD‐box protein once the inorganic phosphate is released (step 5). See Rudoph and Klostermeier (2015) for review
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The DDX5/Dbp2 subfamily acts as RNP chaperone in vivo. The DDX5/Dbp2 subfamily (orange circles, “DEAD”) functions as RNP chaperones in a variety of processes. This includes regulation of lncRNA activities (Cloutier et al., ; Yao et al., ; Zhang et al., ), pre‐mRNA splicing (Z.‐R. Liu, ), alternative splicing (Y. J. Lee, Wang, & Rio, ), mRNA export (Ma et al., ), miRNA processing (Remenyi, Bajan, Fuller‐Pace, Arthur, & Hutvagner, ), nonsense‐mediated decay (NMD) (Geißler, Altmeyer, Stein, Uhlmann‐Schiffler, & Stahl, ), and ribosome biogenesis (Saporita et al., )
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Sequence alignment of the founding DDX5/Dbp2 subfamily members. Multiple sequence alignment of human DDX5 (NP_001307525.1), DDX17 (NP_006377.2), Drosophila Rm62 (NP_524243.2), and S. cerevisiae Dbp2 (NP_014287.3) was conducted using the Clustal Omega web service (McWilliam et al., ). Twelve conserved domains in the helicase core, the RG‐rich regions, and the mammalian‐specific CTE are highlighted with black boxes
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Unrooted phylogenetic tree of human DEAD‐box helicases. Protein sequences of 38 annotated human DEAD‐box proteins were downloaded from NCBI. Multiple sequence alignment and phylogenetic analysis were conducted by MAFFT version 7 (Katoh, Rozewicki, & Yamada, ). Bootstrap values represent the percentage of replicates in which the same branch was recovered during 1,000 times of resampling
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems

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