Nearly all aspects of RNA metabolism, from transcription and translation to mRNA decay, involve RNA helicases, which are enzymes that use ATP to bind or remodel RNA and RNA-protein complexes (ribonucleoprotein (RNP) complexes) 1 . RNA helicases are found in all three domains of life, and many viruses also encode one or more of these proteins 2,3 . Together with the structurally related DNA helicases that function in replication, recombination and repair, the RNA helicases are classified into superfamilies and families, based on sequence and structural features 3,4 . DEAD box proteins form the largest helicase family, with 37 members in humans and 26 in Saccharomyces cerevisiae 3 , and are characterized by the presence of an Asp-Glu-Ala-Asp (DEAD) motif.DEAD box helicases have central and, in many cases, essential physiological roles in cellular RNA metabolism 5 (FIG. 1). The proteins generally function as part of larger multicomponent assemblies, such as the spliceosom e or the eukaryotic translation initiation machinery 6 . Mutations and deregulation of several DEAD box proteins have been linked to disease states, including cancer 7 . Although all DEAD box proteins contain a structurally highly conserved core with conserved ATP-binding and RNA-binding sites, different proteins have been associated with diverse and seemingly unrelated functions, including the disassembly of RNPs, chaperoning during RNA folding and even stabil ization of protein complexes on RNA 5,6 . How these highly conserved proteins fulfil such an array of different functions has been a long-standing question.Research has now started to illuminate the molecular basis for this functional diversity. In this Review, we summarize how structural data, together with biochemical and biophysical studies, have revealed unexpected modes by which these proteins function. We also discuss how novel molecular and cell biological approaches have better defined the cellular roles of DEAD box helicases. We outline our current view on common structural and mechan istic themes that have emerged, and on physical models of how these 'unusual' RNA helicases work.Structures of DEAD box RNA helicases A number of structural studies have universally shown that members of the DEAD box family contain a highly conserved helicase core that harbours the binding sites for ATP and RNA 3,4,8 . The core is surrounded by variable auxiliary domains, which are thought to be critical for the diverse functions of these enzymes.Structure of the helicase core. DEAD box proteins belong to helicase superfamily 2 (SF2) 2 . Similarly to all SF2 helicases, DEAD box proteins are built around a highly conserved helicase core of two virtually identical domains that resemble the bacterial recombination protein recombinase A (RecA) 3,4,8 (FIG. 2a,b). Within this helicase core, at least 12 characteristic sequence motifs are located at conserved positions (FIG. 2a,b). Some of these motifs are conserved across the entire SF2 family, whereas others are found only in the DEAD box family 3 ....

Helicases of the superfamily (SF) 1 and 2 are involved in virtually all aspects of RNA and DNA metabolism. SF1 and SF2 helicases share a catalytic core with high structural similarity, but different enzymes even within each superfamily perform a wide spectrum of distinct functions on diverse substrates. To rationalize similarities and differences between these helicases, we outline a classification based on protein families that are characterized by typical sequence, structural and mechanistic features. This classification complements and extends existing SF1 and SF2 helicase categorizations and highlights major structural and functional themes for these proteins. We discuss recent data in the context of this unifying view of SF1 and SF2 helicases.

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RNA helicases are ubiquitous, highly conserved enzymes that participate in nearly all aspects of RNA metabolism. These proteins bind or remodel RNA or RNA-protein complexes in an ATPdependent fashion. How RNA helicases physically perform their cellular tasks has been a longstanding question, but in recent years, intriguing models have started to link structure, mechanism and biological function for some RNA helicases. This review outlines our current view on major structural and mechanistic themes of RNA helicase function, and on emerging physical models for cellular roles of these enzymes. RNA helicases: ubiquitous and central players in RNA metabolismRNA helicases are highly conserved enzymes that use ATP to bind or remodel RNA or ribonucleoprotein complexes (RNPs) 1 . One of the largest protein classes in RNA metabolism, RNA helicases are found in all kingdoms of life 2 . In eukaryotes these enzymes participate in nearly all aspects of RNA metabolism 1 . RNA helicases have received significant attention, ever since their identification in the 1980s. Many RNA helicases are essential for viability, and a growing number of these enzymes are known to play major regulatory roles in cells 1,3 . Yet, despite important insights into structural, mechanistic, and cellular aspects of their function, it has remained enigmatic how these enzymes physically perform their cellular tasks. The last few years have now seen a notable increase in the number of cell biological, genetic, molecular biological, biochemical-biophysical, and structural studies on RNA helicases. Although much remains to be learned, intriguing models are emerging that start to link structure, mechanism and biological function for some RNA helicases. In this review, I outline our current view on major structural and mechanistic aspects of RNA helicase function, and how these translate into cellular roles for these enzymes. For space reasons, I will focus mainly on the eukaryotic proteins. RNA helicase basics: superfamilies, families, and structural themesRNA helicases are closely related to DNA helicases 4 . Both DNA and RNA helicases fall into two categories, those that form oligomeric (mostly hexameric) rings, and those that do not 5 . Based on sequence and comparative structural and functional analyses, all helicases are classified into six superfamilies (SFs) 5,6 . The ring-forming helicases comprise SFs 3 to 6, and the non-ring forming ones comprise SFs 1 and 2 5 . All eukaryotic RNA helicases belong to SFs 1 and 2 (Fig. 1). Ring-shaped RNA helicases are found in bacteria (e.g. Rho phone: 216.368.3336, exj13@case.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the conte...

Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases led to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes.