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The Discovery of Zinc Fingers and Their Practical Applications in Gene Regulation: A Personal Account

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Zinc Finger Proteins

Part of the book series: Molecular Biology Intelligence Unit ((MBIU))

Abstract

An account is given of the discovery of the classical Cys2His2 (C2H2) zinc finger, arising from biochemical studies on the protein transcription factor IIIA found in Xenopus ooctyes, and of subsequent structural studies on its 3D structure and its interaction with DNA. Each finger is a self-contained domain stabilized by a zinc ion ligated to a pair of cysteines and a pair of histidines, and by an inner structural hydrophobic core. This work showed not only a novel protein fold but also a novel principle of DNA recognition. Whereas other DNA binding proteins generally make use of the symmetry of the double helix, zinc fingers can be linked linearly in tandem to recognize nucleic acid sequences of different lengths. This modular design offers a large number of combinatorial possibilities for the specific recognition of DNA (or RNA). It is therefore not surprising that this zinc finger is found widespread in nature, in 3% of the genes of the human genome.

It had long been the goal of molecular biologists to design DNA binding proteins for specific control of gene expression. It has been demonstrated that the zinc finger design is ideally suited for such purposes, discriminating between closely related sequences both in vitro and in vivo. The first example of the potential of the method was in 1994 when a three-finger protein was constructed to block the expression of an oncogene transformed into a mouse cell line. By fusing zinc finger peptides to repression or activation domains, genes can be selectively switched off and on. Several recent applications are described.

After the initial discovery, other types of zinc-binding domains which fold and interact with DNA or RNA in a different way were found, and these have become loosely grouped under the name of zinc finger proteins.

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Author information

Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Cambridge, UK

    Aaron Klug

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  1. Aaron Klug
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Editors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA

    Shiro Iuchi

  2. Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Natalie Kuldell

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Klug, A. (2005). The Discovery of Zinc Fingers and Their Practical Applications in Gene Regulation: A Personal Account. In: Iuchi, S., Kuldell, N. (eds) Zinc Finger Proteins. Molecular Biology Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/0-387-27421-9_1

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