Multiple modes of RNA recognition by zinc finger proteins

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Zinc finger proteins are generally thought of as DNA-binding transcription factors; however, certain classes of zinc finger proteins, including the common C2H2 zinc fingers, function as RNA-binding proteins. Recent structural studies of the C2H2 zinc fingers of transcription factor IIIA (TFIIIA) and the CCCH zinc fingers of Tis11d in complex with their RNA targets have revealed new modes of zinc finger interaction with nucleic acid. The three C2H2 zinc fingers of TFIIIA use two modes of RNA recognition that differ from the classical mode of DNA recognition, whereas the CCCH zinc fingers of Tis11d recognize specific AU-rich sequences through backbone atom interaction with the Watson–Crick edges of the adenine and uracil bases.

Introduction

The classical C2H2 ‘zinc finger’ proteins were identified 20 years ago as modular nucleic acid recognition elements [1]. Although most noted for their role as DNA-binding transcription factors, C2H2 zinc fingers were identified in transcription factor IIIA (TFIIIA), which was first shown to be the protein component that associates with 5S rRNA within a 7S particle in Xenopus oocytes [2]. Later, its DNA-binding properties were suggested when TFIIIA was shown to regulate expression of the 5S rRNA gene [3]. More recently, the CCCH class of zinc finger protein has been shown to bind to RNA targets [4]. This review will focus on recent structural work illuminating our understanding of C2H2 and CCCH zinc finger protein interaction with RNA. Readers may also be interested in the interaction of the CCHC zinc knuckle domain of a retroviral nucleocapsid protein with a model RNA representing the packaged dimeric RNA genome. These results, from D'Souza and Summers [5••], suggest how the nucleocapsid protein may interact with RNA bases that become unpaired when the genomic DNA forms dimers.

Section snippets

RNA binding by C2H2 zinc finger proteins

TFIIIA in Xenopus oocytes acts as an essential RNA polymerase III transcription factor for the expression of the 5S rRNA gene, binds to 5S rRNA to form a 7S ribonucleoprotein particle that stabilizes the RNA until it is needed for ribosome assembly and facilitates nuclear export of the 5S rRNA [2, 3, 6]. TFIIIA contains nine C2H2 zinc fingers, which are used to recognize RNA and DNA targets — 5S rRNA and the 5S rRNA gene [1]. The C2H2 zinc finger is a module of approximately 30 amino acid

RNA binding by CCCH zinc finger proteins

Tis11d is one of three closely related human proteins that are part of the family of CCCH zinc finger proteins (reviewed recently in [16]). These zinc fingers are characterized by three cysteine residues and one histidine residue that coordinate the zinc ion and form, in general, a Cys-X8-Cys-X5-Cys-X3-His sequence. The prototypic CCCH zinc finger protein is the related protein tristetraprolin (TTP), also known as Tis11, Nup475 or ZFP36. In the zinc finger region, Tis11d is closely related to

Conclusions

Zinc finger domains, although small, appear to be quite versatile. The C2H2 zinc finger scaffold can be used for base-specific recognition of the DNA major groove, backbone recognition of the RNA major groove, and almost customized RNA base and loop recognition. Our understanding of CCCH zinc finger–RNA recognition has just begun with the Tis11d–AU-rich element RNA structure. How versatile a protein backbone can be for RNA (and perhaps DNA or protein) recognition remains to be discovered.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

I am grateful to my colleagues at the National Institute of Environmental Health Sciences (NIEHS) for critical comments on the manuscript, Rachelle Bienstock for providing a coordinate file for B-DNA, and my laboratory for their patience and advice as I prepared this article.

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