Zinc fingers for gripping DNA

by Eric Drexler on 2010/04/16

Zinc-finger protein
Zinc fingers & DNA

From “Toward Modular Molecular
Composite Nanosystems”
[talk slides, pdf]

Zinc finger technology has great promise in genetic engineering and therapeutics, with potential applications in structural DNA nanotechnology, too.

Zinc finger proteins (ZFPs) are often called “game changing” because of the unprecedented way they precisely modify genes. Excitement about them is mirrored in the number of related scientific publications, which have climbed from hardly any 20 years ago to more than 360 in 2009.

Chemical & Engineering News

A ZFP is a sequence of small protein structures (the fingers) that, taken together, bind to a specific DNA sequence. Unlike oligonucleotides, which bind to the Watson-Crick interface of single-stranded DNA, ZFPs bind in the major groove of double-stranded DNA (dsDNA), recognizing DNA base pairs from the side. They’re modular and can be engineered to target sequences chosen by a designer.

This mode of binding enables sequence-specific interactions without prying DNA strands apart, a fundamental advantage in a biological context. Binding dsDNA also opens a range of potential applications in structural DNA nanotechnology because it provides a way to bind protein structures to a dsDNA scaffold at specific sites, and with relatively high rigidity. This is an enabler for the DNA/protein/special-structure approach to modular molecular composite nanosystems.

Each finger binds with a degree of specificity and affinity, but multiple fingers must be stitched together to achieve tight, high-affinity binding to unique sequences. This engineering problem is tractable. There’s an open-source Zinc Finger Consortium (and a zinc-finger design server), as well as a thriving biotechnology company with a fat patent portfolio, Sangamo BioSciences. Sangamo aims to to produce products for medicine.

ZFPs enable a clever trick for editing DNA: A nuclease that cuts dsDNA can be inactivated by splitting into domains that regain activity when brought together. The complementary domains are linked to ZFPs that bind DNA sequences flanking a target site. Where these sequences are found together, both ZFPs bind, bringing the nuclease domains together; these bind, regain function, and cut, leaving the rest of the genome untouched.

This synergistic, cleanly targeted operation can be leveraged to inactivate or edit a selected genetic component with unmatched reliability and specificity. Powerful applications follow.

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