Z-DNA

Z-DNA is one of the many possible double helical structures of DNA. It is a left-handed double helical structure in which the double helix winds to the left in a zig-zag pattern (instead of to the right, like the more common B-DNA form). Z-DNA is thought to be one of three biologically active double helical structures along with A- and B-DNA.

History
Z-DNA was the first single-crystal X-ray structure of a DNA fragment (a self-complementary DNA hexamer d(CG)3). It was resolved as a left-handed double helix with two anti-parallel chains that were held together by Watson-Crick base pairs (see: x-ray crystallography). It was solved by Andrew Wang, Alexander Rich, and co-workers in 1979 at MIT. The crystallisation of a B- to Z-DNA junction in 2005 provided a better understanding of the potential role Z-DNA plays in cells. Whenever a segment of Z-DNA forms, there must be B-Z junctions at its two ends, interfacing it to the B-form of DNA found in the rest of the genome.

In 2007, the RNA version of Z-DNA, Z-RNA, was described as a transformed version of an A-RNA double helix into a left-handed helix. The transition from A-RNA to Z-RNA, however, was already described in 1984.

Structure
Z-DNA is quite different from the right-handed forms. In fact, Z-DNA is often compared against B-DNA in order to illustrate the major differences. The Z-DNA helix is left-handed and has a structure that repeats every 2 base pairs. The major and minor grooves, unlike A- and B-DNA, show little difference in width. Formation of this structure is generally unfavourable, although certain conditions can promote it; such as alternating purine-pyrimidine sequence (especially poly(dGC)2), negative DNA supercoiling or high salt and some cations (all at physiological temperature, 37°C, and pH 7.3-7.4). Z-DNA can form a junction with B-DNA (called a "B-to-Z junction box") in a structure which involves the extrusion of a base pair. The Z-DNA conformation has been difficult to study because it does not exist as a stable feature of the double helix. Instead, it is a transient structure that is occasionally induced by biological activity and then quickly disappears.

Predicting Z-DNA structure
It is possible to predict the likelihood of a DNA sequence forming a Z-DNA structure. An algorithm for predicting the propensity of DNA to flip from the B-form to the Z-form, ZHunt, was written by Dr. P. Shing Ho in 1984 (at MIT). This algorithm was later developed by Tracy Camp, P. Christoph Champ, Sandor Maurice, and Jeffrey M. Vargason for genome-wide mapping of Z-DNA (with P. Shing Ho as the principal investigator).

Z-Hunt is available at Z-Hunt online.

Biological significance
While no definitive biological significance of Z-DNA has been found, it is commonly believed to provide torsional strain relief (supercoiling) while DNA transcription occurs. The potential to form a Z-DNA structure also correlates with regions of active transcription. A comparison of regions with a high sequence-dependent, predicted propensity to form Z-DNA in human chromosome 22 with a selected set of known gene transcription sites suggests there is a correlation.

Z-DNA formed after transcription initiation in some cases may be bound by RNA modifying enzymes, such as ADAR1, which then alter the sequence of the newly-formed RNA.

In 2003, Biophysicist Alexander Rich of the Massachusetts Institute of Technology noticed that a poxvirus virulence factor, called E3L, mimicked a mammalian protein that binds Z-DNA. In 2005, Rich and his colleagues pinned down what E3L does for the poxvirus. When expressed in human cells, E3L increases by five- to 10-fold the production of several genes that block a cell’s ability to self-destruct in response to infection.

Rich speculates that the Z-DNA is necessary for transcription and that E3L stabilizes the Z-DNA, thus prolonging expression of the anti-apoptotic genes. He suggests that a small molecule that interferes with the E3L binding to Z-DNA could thwart the activation of these genes and help protect people from pox infections.