Z-ДНК: Левозакрученная структура ДНК

One of many possible double helical structures of 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 helix winds to the left in a zigzag 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 DNA and B DNA.

Left handed DNA was first proposed by Robert Wells and colleagues, as the structure of a repeating polymer of inosine–cytosine. They observed a "reverse" circular dichroism spectrum for such DNAs, and interpreted this incorrectly to mean that the strands wrapped around one another in a left handed fashion. The relationship between Z DNA and the more familiar B DNA was indicated by the work of Pohl and Jovin, who showed that the ultraviolet circular dichroism of poly(dG dC) was nearly inverted in 4 M sodium chloride solution and that the structure of poly d(I–C)·poly d(I–C) was in fact a right handed D DNA conformation. The suspicion that this was the result of a conversion from B DNA to Z DNA was confirmed by examining the Raman spectra of these solutions and the Z DNA crystals. Subsequently, a crystal structure of "Z DNA" was published which turned out to be 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 antiparallel chains that were held together by Watson–Crick base pairs (see X ray crystallography). It was solved by Andrew H. J. Wang, Alexander Rich, and coworkers 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.

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 other base pair. 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.

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 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 Ho as the principal investigator).

Since the discovery and crystallization of Z DNA in 1979, the configuration has left scientists puzzled about the pathway and mechanism from the B DNA configuration to the Z DNA configuration. The conformational change from B DNA to the Z DNA structure was unknown at the atomic level, but in 2010, computer simulations conducted by Lee et al. were able to computationally determine that the step wise propagation of a B to Z transition would provide a lower energy barrier than the previously hypothesized concerted mechanism. Since this was computationally proven, the pathway would still need to be tested experimentally in the lab for further confirmation and validity, in which Lee et al. specifically states in their journal article, "The current [computational] result could be tested by Single molecule FRET (smFRET) experiments in the future." This was performed by measuring the intensity values between the donor and acceptor fluorescent dyes, also known as Fluorophores, in relation to each other as they exchange electrons, while tagged onto a DNA molecule. The distances between the fluorophores could be used to quantitatively calculate the changes in proximity of the dyes and conformational changes in the DNA. A Z DNA high affinity binding protein, hZαADAR1, was used at varying concentrations to induce the transformation from B DNA to Z DNA. A role in regulating type I interferon responses in cancer is also supported by findings that 40% of a panel of tumors were dependent on the ADAR enzyme for survival. In previous studies, Z DNA was linked to both Alzheimer's disease and systemic lupus erythematosus. To showcase this, a study was conducted on the DNA found in the hippocampus of brains that were normal, moderately affected with Alzheimer's disease, and severely affected with Alzheimer's disease. Through the use of circular dichroism, this study showed the presence of Z DNA in the DNA of those severely affected. In this study it was also found that major portions of the moderately affected DNA was in the B Z intermediate conformation. This is significant because from these findings it was concluded that the transition from B DNA to Z DNA is dependent on the progression of Alzheimer's disease. There are two types of these antibodies. Through radioimmunoassay, it was found that one interacts with the bases exposed on the surface of Z DNA and denatured DNA, while the other exclusively interacts with the zig zag backbone of only Z DNA. Similar to that found in Alzheimer's disease, the antibodies vary depending on the stage of the disease, with maximal antibodies in the most active stages of SLE.

Z DNA is commonly believed to provide torsional strain relief during transcription, and it is associated with negative supercoiling. However, while supercoiling is associated with both DNA transcription and replication, Z DNA formation is primarily linked to the rate of transcription. A study of human chromosome 22 showed a correlation between Z DNA forming regions and promoter regions for nuclear factor I. This suggests that transcription in some human genes may be regulated by Z DNA formation and nuclear factor I activation. Developed behind the pathway of RNA polymerase through negative supercoiling, Z DNA formed via active transcription has been shown to increase genetic instability, creating a propensity towards mutagenesis near promoters. A study on Escherichia coli found that gene deletions spontaneously occur in plasmid regions containing Z DNA forming sequences. In mammalian cells, the presence of such sequences was found to produce large genomic fragment deletions due to chromosomal double strand breaks. Both of these genetic modifications have been linked to the gene translocations found in cancers such as leukemia and lymphoma, since breakage regions in tumor cells have been plotted around Z DNA forming sequences.