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Cellular functions of eukaryotic RNA helicases and their links to human diseases

Nature Reviews Molecular Cell Biology volume 24, pages 749–769 (2023)Cite this article

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Abstract

RNA helicases are highly conserved proteins that use nucleoside triphosphates to bind or remodel RNA, RNA–protein complexes or both. RNA helicases are classified into the DEAD-box, DEAH/RHA, Ski2-like, Upf1-like and RIG-I families, and are the largest class of enzymes active in eukaryotic RNA metabolism — virtually all aspects of gene expression and its regulation involve RNA helicases. Mutation and dysregulation of these enzymes have been linked to a multitude of diseases, including cancer and neurological disorders. In this Review, we discuss the regulation and functional mechanisms of RNA helicases and their roles in eukaryotic RNA metabolism, including in transcription regulation, pre-mRNA splicing, ribosome assembly, translation and RNA decay. We highlight intriguing models that link helicase structure, mechanisms of function (such as local strand unwinding, translocation, winching, RNA clamping and displacing RNA-binding proteins) and biological roles, including emerging connections between RNA helicases and cellular condensates formed through liquid–liquid phase separation. We also discuss associations of RNA helicases with human diseases and recent efforts towards the design of small-molecule inhibitors of these pivotal regulators of eukaryotic gene expression.

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Fig. 1: Characteristics of RNA helicases.
Fig. 2: Mechanisms of function of RNA helicases.
Fig. 3: Regulation of helicase functions.
Fig. 4: Roles of RNA helicases in pre-mRNA splicing.
Fig. 5: Roles of RNA helicases in translation and RNA decay.
Fig. 6: Functions of RNA helicases in ribosome assembly.
Fig. 7: RNA helicases in viral infections and RNP granule (dis)assembly.

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Acknowledgements

The authors thank J. D. Gallesio for help with preparation of figures. The authors acknowledge funding by the Deutsche Forschungsgemeinschaft (DFG) via SFB1565 (Projektnummer 469281184; P06 to M.T.B. and P12 to K.E.B.). Work in the Jankowsky group is funded by the NIH (GM118088–05).

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Author notes

  1. Eckhard Jankowsky

    Present address: Moderna, Cambridge, MA, USA

Authors and Affiliations

  1. Department of Molecular Biology, University Medical Center Göttingen, Göttingen, Germany

    Katherine E. Bohnsack & Markus T. Bohnsack

  2. Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Soon Yi, Sarah Venus & Eckhard Jankowsky

  3. Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Soon Yi, Sarah Venus & Eckhard Jankowsky

  4. Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Eckhard Jankowsky

  5. Göttingen Centre for Molecular Biosciences, University of Göttingen, Göttingen, Germany

    Markus T. Bohnsack

  6. Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany

    Markus T. Bohnsack

Authors
  1. Katherine E. Bohnsack
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Contributions

K.E.B., M.T.B. and E.J. conceptualized the article, and all authors contributed to preparing the manuscript, figures and tables.

Corresponding authors

Correspondence to Katherine E. Bohnsack, Eckhard Jankowsky or Markus T. Bohnsack.

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E.J. is an employee and owns equity of Moderna. The other authors declare no competing interests.

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Nature Reviews Molecular Cell Biology thanks Katrin Karbstein, Vladimir Pena, and Stephen Floor with Jess Sheu-Gruttadauria, for their contribution to the peer review of this work.

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Supplementary information

Glossary

43S pre-initiation complex

(43S PIC). A ribonucleoprotein complex containing the small ribosomal subunit and translation initiation factors.

ATPase cycle

Cycle in which ATP bound by an enzyme is hydrolysed, ADP and Pi are released before ATP re-associates, and the steps are repeated.

Branch point

Nucleotide located within a short motif upstream of the 3′ splice site; the branch point nucleotide initiates a nucleophilic attack on the 5′ splice site to form an intron lariat.

Caspase activation and recruitment domains

(CARDs). Protein domains that mediate protein–protein interactions to activate signalling pathways in apoptosis, inflammation and innate immunity.

Codon optimality

The use of codons for optimal translation efficiency; a balance is required between the demand for different aminoacylated tRNAs by translating ribosomes and their availability in the cytoplasm.

Exon junction complex

(EJC). A protein complex that assembles 20 to 24 nucleotides upstream of exon–exon junctions during pre-mRNA splicing and remains bound to the mature mRNA to regulate export, translation and nonsense-mediated decay. The EJC is ejected during the first round of protein synthesis.

Exosome

A protein complex that degrades RNAs through endoribonucleolytic and 3′−5′ exoribonucleolytic activity.

Glucocorticoid receptor-mediated decay

mRNA degradation pathway in which the glucocorticoid receptor binds an mRNA transcript and, upon binding to glucocorticoid, recruits PNRC2 and UPF1 to initiate mRNA degradation.

Histone mRNA decay

Degradation pathway specific to histone mRNAs, which lack poly(A) tails. UPF1 is recruited to a conserved stem–loop structure in the 3′ untranslated region of histone mRNAs by a stem–loop binding protein and initiates histone mRNA degradation.

Intrinsically disordered regions

(IDRs). Protein regions without a defined secondary or tertiary structure.

Liquid–liquid phase separation

(LLPS). Phase separation (de-mixing) of protein, RNA and/or other macromolecules resulting in formation of dynamic liquid condensates, which can function as membraneless cellular compartments.

Long non-coding RNAs

A class of RNAs that are longer than 200 nucleotides and generally do not encode proteins.

Nonsense-mediated mRNA decay

(NMD). mRNA degradation pathway in which an mRNA with a premature termination codon is recognized and degraded.

Regnase 1-mediated decay

mRNA degradation pathway of immune homeostasis in which regnase 1 is recruited to a 3′ untranslated region decay element and, together with UPF1, initiates mRNA degradation.

R-loops

Nucleic acid structures consisting of a DNA–RNA hybrid and a displaced single strand of DNA; commonly associated with the function of RNA polymerases.

RNA chaperones

Proteins that facilitate RNA folding into appropriate secondary or tertiary structures by preventing assembly of aberrant structures, promoting formation of correct structures, displacing bound proteins and/or resolving misfolding.

RNA-induced silencing complexes

(RISCs). Heterogeneous ribonucleoprotein complexes, each containing a microRNA and Argonaute protein, that regulate mRNA expression at transcriptional and translational levels.

RNA remodelling

Dynamic alteration of the secondary or tertiary structure of RNA molecules.

Small nuclear RNA

(snRNA). A class of nuclear non-coding RNAs of 100–1200 nucleotides that form spliceosome complexes with partnering proteins.

Small nucleolar RNAs

(snoRNAs). A class of nucleolar non-coding RNAs of 60–300 nucleotides that guide methylation, pseudouridylation and acetylation of ribosomal (and other) RNAs, or that chaperone RNA folding.

Staufen-mediated decay

mRNA degradation pathway in which the double-stranded RNA-binding protein Staufen binds to a stem–loop structure in the mRNA 3′ untranslated region and recruits UPF1 to initiate mRNA degradation.

TRAMP

(TRF4–TRF45–AIR2–MTR4 polyadenylation). A protein complex that appends short polyadenine tails to the 3′ end of several non-coding RNAs.

TSN-mediated miRNA decay

MicroRNA (miRNA) degradation pathway in which the endoribonuclease translin (TSN) degrades a specific subset of miRNAs. UPF1 promotes dissociation of miRNAs from their targets, thereby rendering the miRNAs more susceptible to TSN-mediated miRNA decay.

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Bohnsack, K.E., Yi, S., Venus, S. et al. Cellular functions of eukaryotic RNA helicases and their links to human diseases. Nat Rev Mol Cell Biol 24, 749–769 (2023). https://doi.org/10.1038/s41580-023-00628-5

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