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The structure, function and evolution of proteins that bind DNA and RNA

Nature Reviews Molecular Cell Biology volume 15, pages 749–760 (2014)Cite this article

Subjects

Key Points

  • DNA- and RNA-binding proteins (DRBPs) constitute a significant fraction of cellular proteins and have important roles in cells. Their functions include control of transcription and translation, DNA repair, splicing, apoptosis and mediating stress responses.

  • Orthogonal binding of DNA and RNA provides an opportunity for competitive regulation of transcription by decoy RNAs, which can be mRNAs, tRNAs and long non-coding RNAs (lncRNAs). Simultaneous binding of DNA and RNA facilitates the assembly of RNA-tethered transcriptional complexes, allowing the recruitment of RNA-containing complexes to specific DNA loci.

  • Binding to both DNA and RNA enables DRBPs to integrate multiple signals into cellular signalling networks and allows improved gene targeting, finer control of gene expression and incorporation of metabolic states or stresses to modulate protein activity.

  • The structural features of DRBPs have been remarkably well conserved during evolution, indicating that dual nucleic acid binding confers selective advantages. DRBPs may have less stringent criteria for interacting with nucleic acids or may adjust their structure when DNA and RNA compete for the same DRBP interaction surface.

  • Nucleic acid sequence evolution has an important role in the development of DRBP function. Emerging studies of rapidly evolving lncRNAs suggest that RNA binding by proteins that were previously thought of as DNA-specific may be a widespread phenomenon.

Abstract

Proteins that bind both DNA and RNA typify the ability of a single gene product to perform multiple functions. Such DNA- and RNA-binding proteins (DRBPs) have unique functional characteristics that stem from their specific structural features; these developed early in evolution and are widely conserved. Proteins that bind RNA have typically been considered as functionally distinct from proteins that bind DNA and studied independently. This practice is becoming outdated, in partly owing to the discovery of long non-coding RNAs (lncRNAs) that target DNA-binding proteins. Consequently, DRBPs were found to regulate many cellular processes, including transcription, translation, gene silencing, microRNA biogenesis and telomere maintenance.

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Figure 1: Defining human DRBPs.
Figure 2: Functional and structural properties of DRBPs.
Figure 3: Three archetypes of DRBP function.
Figure 4: The structural basis for dual DNA and RNA recognition by TDP43 and by the NF-κB subunit p50.
Figure 5: DNA methyltransferases target both DNA and RNA.

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Acknowledgements

W.H.H. is supported by American Heart Association predoctoral fellowship 13PRE16920012 and by a US National Institutes of Health (NIH) training grant to Emory University (5T32GM008602-14). Work in the laboratory of E.A.O. is supported by grant R01DK095750 from the NIH National Institute of Diabetes and Digestive and Kidney Diseases and by grant 14GRNT20460124 from the American Heart Association.

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  1. Department of Biochemistry, Emory University School of Medicine, Atlanta, 30033, Georgia, USA

    William H. Hudson & Eric A. Ortlund

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Correspondence to Eric A. Ortlund.

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Human proteins demonstrated to bind DNA and RNA. (PDF 983 kb)

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DATABASE

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GO:0003723

GO:0003677

FURTHER INFORMATION

Unpublished structure of TDP43 RRMs

Glossary

Rossmann fold

A common protein-folding pattern that contains the topology of a β-α-β fold. It is found in many nucleotide- binding proteins.

Drosha

A nuclease of the RNase III family that, as part of a complex, cleaves primary microRNA (pri-miRNA) transcripts into precursor miRNAs (pre-miRNAs) in the nucleus.

Primary miRNA

(Pri-miRNA). The primary transcripts of microRNA-encoding genes, which are stem–loop structures processed by the Drosha complex into precursor miRNAs (pre-miRNAs). Typical pri-miRNAs are hundreds of base pairs long and can contain several pre-miRNAs.

Precursor miRNA

(Pre-miRNA). The product of Drosha-mediated cleavage of primary microRNAs (pri-miRNAs). Stem–loop-structured pre-miRNAs are exported to the cytoplasm and further processed by Dicer to fully mature miRNAs.

MAD homology 1 domain

An evolutionarily conserved domain found in SMAD proteins. It contains four α-helices, six short β-strands and five loops, and it recognizes specific DNA sequences.

Homeodomain

A protein structural domain that binds DNA and RNA, and that is found most commonly in transcription factors. It consists of a helix–turn–helix structure of 60 amino acids.

GAR domain

A Gly- and Arg-rich motif that adopts a repeated β-turn structure. It is found most commonly in proteins that bind RNA.

Zinc-finger domains

Structural motifs that are characterized by the coordination of one or more zinc ions. There are several different zinc-finger motifs, and each displays a different binding mode and structure.

WW domains

Small protein motifs of 40 amino acids that mediate specific protein–protein interactions with short Pro-rich or Pro-containing motifs.

Ftz-F1 domain

A protein domain first identified in the Fushi Tarazu factor 1 (FTZ-F1) nuclear receptor. It contains an evolutionarily conserved LXXLL motif that recognizes other LXXLL-related motifs.

K-homology domain

A conserved protein domain that interacts with both RNA and DNA through a binding cleft formed between two α-helices, two β-sheets and the GXXG loop.

Cold-shock domain

(CSD). A small (∼ 70 kDa) domain with high similarity to the ribonucleoprotein 1 RNA-binding motif. This domain is found in DNA- and RNA-binding proteins in bacteria, archaea and eukaryotes.

Interfaces

The solvent-accessible portions of a protein that are capable of binding a ligand — including DNA and RNA — in a competitive or non-competitive manner.

π-stacking interactions

Non-covalent interactions between two aromatic molecules owing to the attractive force originating from the opposing electrostatic potentials between two adjacent aromatic amino acid residues.

Aptamers

Single-stranded DNA or RNA molecules that selectively bind small molecules, proteins and peptides with high affinity. Aptamers have dynamic tertiary structures, which contribute to the diversity of their binding targets.

Z-DNA

DNA in the conformation of a left-handed double helix.

Z-RNA

RNA in the conformation of a left-handed double helix.

Y box

A DNA target sequence with the consensus CTGATTG, which is recognized and bound by certain proteins.

RNA homopolymers

Sequences of ribonucleotides consisting of a single base; for example, CCCCCCCCC.

Intrinsically disordered protein

A protein that does not have a well-ordered three-dimensional structure, such as proteins containing random coils or multiple domains connected with flexible linkers.

Systematic evolution of ligands by exponential enrichment

(SELEX). A technique to identify ligand-binding-sequence specificity that is based on sequential rounds of binding of an oligonucleotide library to the ligand, followed by PCR amplification of the bound sequences.

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Hudson, W., Ortlund, E. The structure, function and evolution of proteins that bind DNA and RNA. Nat Rev Mol Cell Biol 15, 749–760 (2014). https://doi.org/10.1038/nrm3884

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