Editing Z-DNA

{{Short description|One of many possible double helical structures of DNA}}
[[Image:Z-DNA orbit animated small.gif|right|frame|The Z-DNA structure. {{Proteopedia|Z-DNA}}]]
'''Z-DNA''' is one of the many possible [[double helix|double helical]] structures of [[DNA]]. It is a [[chirality|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]].

==History==
Left-handed DNA was first proposed by [[Robert Wells (biochemist)|Robert Wells]] and colleagues, as the structure of a repeating [[polymer]] of [[inosine]]–[[cytosine]].<ref>{{cite journal |last1=Mitsui |first1=Y. |last2=Langridge |first2=R. |last3=Shortle |first3=B. E. |last4=Cantor |first4=C. R. |last5=Grant |first5=R. C. |last6=Kodama |first6=M. |last7=Wells |first7=R. D. |title=Physical and enzymatic studies on poly d(I–C)·poly d(I–C), an unusual double-helical DNA |journal=Nature |volume=228 |issue=5277 |pages=1166–1169 |year=1970 |pmid=4321098 |doi=10.1038/2281166a0|bibcode=1970Natur.228.1166M |s2cid=4248932 }}</ref> 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,<ref>{{cite journal |last1=Pohl |first1=F. M. |last2=Jovin |first2=T. M. |title=Salt-induced co-operative conformational change of a synthetic DNA: equilibrium and kinetic studies with poly(dG-dC) |journal=Journal of Molecular Biology |volume=67 |pages=375–396 |year=1972 |pmid=5045303 |doi=10.1016/0022-2836(72)90457-3 |issue=3}}</ref> who showed that the [[ultraviolet]] circular dichroism of poly(dG-dC) was nearly inverted in [[Molarity|4&nbsp;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 spectroscopy|Raman spectra]] of these solutions and the Z-DNA crystals.<ref>{{cite journal |last1=Thamann |first1=T. J. |last2=Lord |first2=R. C. |last3=Wang |first3=A. H. |last4=Rich |first4=A. |title=High salt form of poly(dG–dC)·poly(dG–dC) is left handed Z-DNA: raman spectra of crystals and solutions |journal=Nucleic Acids Research |volume=9 |pages=5443–5457 |year=1981 |pmid=7301594 |doi=10.1093/nar/9.20.5443 |issue=20 |pmc=327531}}</ref> 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)<sub>3</sub>). It was resolved as a left-handed double helix with two [[Antiparallel (biochemistry)|antiparallel]] chains that were held together by Watson–Crick [[base pair]]s (see [[X-ray crystallography]]). It was solved by [[Andrew H. J. Wang]], [[Alexander Rich]], and coworkers in 1979 at [[Massachusetts Institute of Technology|MIT]].<ref name=Wang1979>{{cite journal 
|last1=Wang |first1=A. H. |last2=Quigley |first2=G. J. |last3=Kolpak |first3=F. J. |last4=Crawford |first4=J. L. |last5=van Boom |first5=J. H. |last6=van der Marel |first6=G. |last7=Rich |first7=A. |title=Molecular structure of a left-handed double helical DNA fragment at atomic resolution |journal=Nature |volume=282 |pages=680–686 |year=1979 |doi=10.1038/282680a0 |pmid=514347 |issue=5740 |bibcode=1979Natur.282..680W|s2cid=4337955 }}</ref> The crystallisation of a B- to Z-DNA junction in 2005<ref name=Ha2005>{{cite journal|last1=Ha |first1=S. C. |last2=Lowenhaupt |first2=K. |last3=Rich |first3=A. |last4=Kim |first4=Y. G. |last5=Kim |first5=K. K. |title=Crystal structure of a junction between B-DNA and Z-DNA reveals two extruded bases |journal=Nature |volume=437 |issue=7062 |pages=1183–1186 |year=2005 |doi=10.1038/nature04088 |pmid=16237447 |bibcode=2005Natur.437.1183H|s2cid=2539819 }}</ref> 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.<ref name="Placido2007">{{cite journal|title=A left-handed RNA double helix bound by the Zalpha domain of the RNA-editing enzyme ADAR1 |last1=Placido |first1=D. |last2=Brown |first2=B. A. II|last3=Lowenhaupt |first3=K. |last4=Rich |first4=A. |last5=Athanasiadis |first5=A. |journal=Structure |volume=15 |issue=4 |pages=395–404 |year=2007 |pmid=17437712 |doi=10.1016/j.str.2007.03.001 |pmc=2082211}}</ref> The transition from A-RNA to Z-RNA, however, was already described in 1984.<ref name="Hall1984">{{cite journal|title='Z-RNA'—a left-handed RNA double helix |last1=Hall |first1=K. |last2=Cruz |first2=P. |last3=Tinoco |first3=I. Jr |last4=Jovin |first4=T. M. |last5=van de Sande |first5=J. H. |journal=Nature |volume=311 |issue=5986 |pages=584–586 |date=Oct 1984 |pmid=6482970 |doi=10.1038/311584a0 |bibcode = 1984Natur.311..584H |s2cid=4316862 }}</ref>

==Structure==
[[Image:B-, Z-DNA junction 2ACJ.png|right|thumb|B–Z junction bound to a Z-DNA binding domain. Note the two highlighted extruded bases. From {{PDB|2ACJ}}.]]
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)<sub>2</sub>), negative [[DNA supercoil]]ing or high salt and some [[cation]]s (all at physiological temperature, 37&nbsp;°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.<ref name="deRosaM2010">{{cite journal |last1=de Rosa |first1=M. |last2=de Sanctis |first2=D. |last3=Rosario |first3=A. L. |last4=Archer |first4=M. |last5=Rich |first5=A. |last6=Athanasiadis |first6=A. |last7=Carrondo |first7=M. A. |title=Crystal structure of a junction between two Z-DNA helices |journal=Proceedings of the National Academy of Sciences |date=May 2010 |volume=107 |issue=20 |pages=9088–9092 |pmid=20439751 |pmc=2889044 |doi=10.1073/pnas.1003182107 |bibcode = 2010PNAS..107.9088D |doi-access=free }}</ref> 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.<ref name="ZhangH2006">{{cite journal|last1=Zhang |first1=H. |last2=Yu |first2=H. |last3=Ren |first3=J. |last4=Qu |first4=X. |title=Reversible B/Z-DNA transition under the low salt condition and non-B-form poly(dA)poly(dT) selectivity by a cubane-like europium-<small>L</small>-aspartic acid complex |journal=Biophysical Journal |volume=90 |pages=3203–3207 |year=2006 |doi=10.1529/biophysj.105.078402 |url=http://www.biophysj.org/cgi/content/full/90/9/3203 |pmid=16473901 |issue=9 |pmc=1432110 |bibcode = 2006BpJ....90.3203Z }}</ref>

===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 [[P. Shing Ho]] in 1984 at [[Massachusetts Institute of Technology|MIT]].<ref name="pmid3780676">{{cite journal |last1=Ho |first1=P. S. |last2=Ellison |first2=M. J. |last3=Quigley |first3=G. J. |last4=Rich |first4=A. |title=A computer aided thermodynamic approach for predicting the formation of Z-DNA in naturally occurring sequences |journal=EMBO Journal |year=1986 |volume=5 |issue=10 |pages=2737–2744 |pmid=3780676 |pmc=1167176|doi=10.1002/j.1460-2075.1986.tb04558.x }}</ref> 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).<ref name=Champ2004>{{cite journal |last1=Champ |first1=P. C. |last2=Maurice |first2=S. |last3=Vargason |first3=J. M. |last4=Camp |first4=T. |last5=Ho |first5=P. S. |title=Distributions of Z-DNA and nuclear factor I in human chromosome 22: a model for coupled transcriptional regulation |journal=Nucleic Acids Research |volume=32 |issue=22 |pages=6501–6510 |year=2004 |pmid=15598822 |doi=10.1093/nar/gkh988 |pmc=545456}}</ref>

=== Pathway of formation of Z-DNA from B-DNA ===

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.<ref>{{Cite journal|last1=Wang|first1=Andrew H.-J.|last2=Quigley|first2=Gary J.|last3=Kolpak|first3=Francis J.|last4=Crawford|first4=James L.|last5=van Boom|first5=Jacques H.|last6=van der Marel|first6=Gijs|last7=Rich|first7=Alexander|date=December 1979|title=Molecular structure of a left-handed double helical DNA fragment at atomic resolution|journal=Nature|volume=282|issue=5740|pages=680–686|doi=10.1038/282680a0|issn=0028-0836|pmid=514347|bibcode=1979Natur.282..680W|s2cid=4337955}}</ref> 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 [[activation energy|energy barrier]] than the previously hypothesized concerted mechanism.<ref name=":0">{{Cite journal|last1=Lee|first1=Juyong|last2=Kim|first2=Yang-Gyun|last3=Kim|first3=Kyeong Kyu|last4=Seok|first4=Chaok|date=2010-08-05|title=Transition between B-DNA and Z-DNA: Free Energy Landscape for the B−Z Junction Propagation|journal=The Journal of Physical Chemistry B|volume=114|issue=30|pages=9872–9881|doi=10.1021/jp103419t|pmid=20666528|issn=1520-6106|citeseerx=10.1.1.610.1717}}</ref> 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."<ref name=":0" /> In 2018, the pathway from B-DNA to Z-DNA was experimentally proven using smFRET assays.<ref name=":3">{{Cite journal|last1=Kim|first1=Sook Ho|last2=Lim|first2=So-Hee|last3=Lee|first3=Ae-Ree|last4=Kwon|first4=Do Hoon|last5=Song|first5=Hyun Kyu|last6=Lee|first6=Joon-Hwa|last7=Cho|first7=Minhaeng|last8=Johner|first8=Albert|last9=Lee|first9=Nam-Kyung|date=2018-03-23|title=Unveiling the pathway to Z-DNA in the protein-induced B–Z transition|journal=Nucleic Acids Research|volume=46|issue=8|pages=4129–4137|doi=10.1093/nar/gky200|issn=0305-1048|pmc=5934635|pmid=29584891}}</ref> This was performed by measuring the intensity values between the donor and acceptor fluorescent dyes, also known as [[Fluorophore]]s, in relation to each other as they exchange electrons, while tagged onto a DNA molecule.<ref>{{Cite journal|last1=Cooper|first1=David|last2=Uhm|first2=Heui|last3=Tauzin|first3=Lawrence J.|last4=Poddar|first4=Nitesh|last5=Landes|first5=Christy F.|date=2013-06-03|title=Photobleaching Lifetimes of Cyanine Fluorophores Used for Single-Molecule Förster Resonance Energy Transfer in the Presence of Various Photoprotection Systems|journal=ChemBioChem|volume=14|issue=9|pages=1075–1080|doi=10.1002/cbic.201300030|pmc=3871170|issn=1439-4227|pmid=23733413}}</ref><ref>{{Cite journal|last=Didenko|first=Vladimir V.|date=November 2001|title=DNA Probes Using Fluorescence Resonance Energy Transfer (FRET): Designs and Applications|journal=BioTechniques|volume=31|issue=5|pages=1106–1121|doi=10.2144/01315rv02|issn=0736-6205|pmc=1941713|pmid=11730017}}</ref> 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 [[DNA-binding protein|binding protein]], hZαADAR1,<ref>{{Cite journal|last1=Herbert|first1=A.|last2=Alfken|first2=J.|last3=Kim|first3=Y.-G.|last4=Mian|first4=I. S.|last5=Nishikura|first5=K.|last6=Rich|first6=A.|date=1997-08-05|title=A Z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase|journal=Proceedings of the National Academy of Sciences|volume=94|issue=16|pages=8421–8426|doi=10.1073/pnas.94.16.8421|issn=0027-8424|pmc=22942|pmid=9237992|bibcode=1997PNAS...94.8421H|doi-access=free}}</ref> was used at varying concentrations to induce the transformation from B-DNA to Z-DNA.<ref name=":3" /> The smFRET assays revealed a B* transition state, which formed as the binding of hZαADAR1 accumulated on the B-DNA structure and stabilized it.<ref name=":3" /> This step occurs to avoid high junction energy, in which the B-DNA structure is allowed to undergo a conformational change to the Z-DNA structure without a major, disruptive change in energy. This result coincides with the computational results of Lee et al. proving the mechanism to be step-wise and its purpose being that it provides a lower energy barrier for the conformational change from the B-DNA to Z-DNA configuration.<ref name=":0" /> Contrary to the previous notion, the binding proteins do not actually stabilize the Z-DNA conformation after it is formed, but instead they actually promote the formation of the Z-DNA directly from the B* conformation, which is formed by the B-DNA structure being bound by high affinity proteins.<ref name=":3" />

==Biological significance==
A biological role for Z-DNA in the regulation of type I interferon responses has been confirmed in studies of three well-characterized rare Mendelian Diseases: Dyschromatosis Symmetrica Hereditaria (OMIM: 127400), Aicardi-Goutières syndrome (OMIM: 615010) and Bilateral Striatal Necrosis/Dystonia. Families with haploid ADAR transcriptome enabled mapping of Zα variants directly to disease, showing that genetic information is encoded in DNA by both shape and sequence.<ref name="Herbert 2019 114–117">{{cite journal|last=Herbert|first=A.|title=Mendelian disease caused by variants affecting recognition of Z-DNA and Z-RNA by the Zα domain of the double-stranded RNA editing enzyme ADAR. |journal=European Journal of Human Genetics |volume= 8|pages= 114–117|year=2019 |issue=1|pmid=31320745 |doi=10.1038/s41431-019-0458-6 |pmc=6906422}}</ref> 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.<ref>{{cite journal|last=Herbert|first=A.|title=ADAR and Immune Silencing in Cancer. |journal=Trends in Cancer |volume= 5|issue=5 |pages=272–282 |year=2019 |pmid=31174840 |doi=10.1016/j.trecan.2019.03.004|s2cid=155209484 }}</ref>

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.<ref name=":2">{{Cite journal|last1=Suram|first1=Anitha|last2=Rao|first2=Jagannatha K. S.|last3=S.|first3=Latha K.|last4=A.|first4=Viswamitra M.|date=2002|title=First Evidence to Show the Topological Change of DNA from B-DNA to Z-DNA Conformation in the Hippocampus of Alzheimer's Brain|journal=NeuroMolecular Medicine|volume=2|issue=3|pages=289–298|doi=10.1385/nmm:2:3:289|pmid=12622407|s2cid=29059186|issn=1535-1084}}</ref> 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.<ref name=":2" /> Additionally, Z-DNA is associated with systemic lupus erythematosus (SLE) through the presence of naturally occurring antibodies. Significant amounts of anti Z-DNA antibodies were found in SLE patients and were not present in other rheumatic diseases.<ref>{{Cite journal|last1=Lafer|first1=E M|last2=Valle|first2=R P|last3=Möller|first3=A|last4=Nordheim|first4=A|last5=Schur|first5=P H|last6=Rich|first6=A|last7=Stollar|first7=B D|date=1983-02-01|title=Z-DNA-specific antibodies in human systemic lupus erythematosus.|journal=Journal of Clinical Investigation|volume=71|issue=2|pages=314–321|doi=10.1172/jci110771|issn=0021-9738|pmc=436869|pmid=6822666}}</ref> 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 in transcription ===
Z-DNA is commonly believed to provide [[Strain (chemistry)#Torsional strain|torsional strain]] relief during [[DNA transcription|transcription]], and it is associated with [[DNA supercoiling|negative supercoiling]].<ref name="Ha2005" /><ref name="Rich2003">{{cite journal  |last1=Rich |first1=A |last2=Zhang |first2=S |year=2003 |title=Timeline: Z-DNA: the long road to biological function  |journal=Nature Reviews Genetics |volume=4 |issue=7 |pages=566–572 |pmid=12838348 |doi=10.1038/nrg1115|s2cid=835548 }}</ref> However, while supercoiling is associated with both DNA transcription and replication, Z-DNA formation is primarily linked to the rate of [[transcription (biology)|transcription]].<ref>{{cite journal|last1=Wittig|first1=B.|last2=Dorbic|first2=T.|last3=Rich|first3=A.|title=Transcription is associated with Z-DNA formation in metabolically active permeabilized mammalian cell nuclei |journal=Proceedings of the National Academy of Sciences |volume=88 |issue=6 |pages=2259–2263 |year=1991 |pmid=2006166 |doi=10.1073/pnas.88.6.2259|pmc=51210|bibcode=1991PNAS...88.2259W|doi-access=free}}</ref>

A study of [[Chromosome 22 (human)|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.<ref name=Champ2004/>

Z-DNA sequences upstream of promoter regions have been shown to stimulate transcription.  The greatest increase in activity is observed when the Z-DNA sequence is placed three helical turns after the [[Promoter (genetics)|promoter sequence]]. Furthermore, using micrococcal nuclease-crosslinking technique,<ref name=":5" /> Z-DNA is unlikely to form [[nucleosome]]s, which are often located before and/or after a Z-DNA forming sequence.  Because of this property, Z-DNA is hypothesized to code for the boundary in nucleosome positioning.  Since the placement of nucleosomes influences the binding of [[transcription factor]]s, Z-DNA is thought to regulate the rate of transcription.<ref name=":5">{{cite journal |last1=Wong|first1=B.|last2=Chen|first2=S.|last3=Kwon|first3=J.-A.|last4=Rich|first4=A.|title=Characterization of Z-DNA as a nucleosome-boundary element in yeast ''Saccharomyces cerevisiae''|journal=Proceedings of the National Academy of Sciences |volume=104 |issue=7 |pages=2229–2234 |year=2007 |pmid=17284586 |doi=10.1073/pnas.0611447104|pmc=1892989|bibcode=2007PNAS..104.2229W|doi-access=free}}</ref>

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.<ref name="Wang2006">{{cite journal |last1=Wang|first1=G.|last2=Christensen|first2=L. A.|last3=Vasquez|first3=K. M.|title=Z-DNA-forming sequences generate large-scale deletions in mammalian cells |journal=Proceedings of the National Academy of Sciences |volume=108 |issue=8 |pages=2677–2682 |year=2006 |pmid=16473937 |doi=10.1073/pnas.0511084103|pmc=1413824|bibcode=2006PNAS..103.2677W|doi-access=free}}</ref> A study on ''[[Escherichia coli]]'' found that gene [[Deletion (genetics)|deletions]] spontaneously occur in [[plasmid]] regions containing Z-DNA-forming sequences.<ref name="Freund1989">{{cite journal |last1=Freund |first1=A. M.|last2=Bichara|first2=M.|last3=Fuchs|first3=R. P.|title=Z-DNA-forming sequences are spontaneous deletion hot spots |journal=Proceedings of the National Academy of Sciences |volume=86 |issue=19 |pages=7465–7469 |year=1989 |pmid=2552445|doi=10.1073/pnas.86.19.7465 |pmc=298085|bibcode=1989PNAS...86.7465F|doi-access=free}}</ref> In mammalian cells, the presence of such sequences was found to produce large genomic fragment deletions due to chromosomal [[DNA repair|double-strand breaks]]. Both of these genetic modifications have been linked to the [[Chromosomal translocation|gene translocations]] found in cancers such as [[leukemia]] and [[lymphoma]], since breakage regions in [[tumor cell]]s have been plotted around Z-DNA-forming sequences.<ref name="Wang2006" /> However, the smaller deletions in bacterial plasmids have been associated with [[replication slippage]], while the larger deletions associated with mammalian cells are caused by [[non-homologous end-joining]] repair, which is known to be prone to error.<ref name="Wang2006" /><ref name="Freund1989" />

The toxic effect of [[ethidium bromide]] (EtBr) on [[trypanosoma]]s is caused by shift of their [[kinetoplast]]id DNA to Z-form. The shift is caused by [[intercalation (biochemistry)|intercalation]] of EtBr and subsequent loosening of DNA structure that leads to unwinding of DNA, shift to Z-form and inhibition of DNA replication.<ref name="pmid21187912">{{cite journal |last1= Roy Chowdhury |first1 = A. |last2=Bakshi |first2=R.|last3=Wang |first3=J. |last4=Yıldırır |first4=G. |last5=Liu |first5=B. |last6=Pappas-Brown |first6=V. |last7=Tolun |first7=G. |last8=Griffith |first8=J. D. |last9=Shapiro |first9=T. A. |last10=Jensen |first10=R. E. |last11=Englund |first11=P. T. | title = The killing of African trypanosomes by ethidium bromide | journal = PLOS Pathogens | volume = 6 | issue = 12 | pages = e1001226 | date = Dec 2010 | pmid = 21187912 | pmc = 3002999 | doi = 10.1371/journal.ppat.1001226 |doi-access = free }}</ref>

=== Discovery of the Zα domain ===
The first domain to bind Z-DNA with high affinity was discovered in [[ADAR|ADAR1]] using an approach developed by Alan Herbert.<ref name="Herbert1993">{{cite journal |last1=Herbert |first1=A. |last2=Rich |first2=A. |year=1993 |title=A method to identify and characterize Z-DNA binding proteins using a linear oligodeoxynucleotide |journal=Nucleic Acids Research |volume=21 |issue=11 |pages=2669–2672 |pmid=8332463 |pmc= 309597 |doi=10.1093/nar/21.11.2669}}</ref><ref name="Herbert1997">{{cite journal |last1=Herbert |first1=A. |last2=Alfken |first2=J. |last3=Kim |first3=Y. G. |last4=Mian |first4=I. S. |last5=Nishikura |first5=K. |last6=Rich |first6=A. |year=1997 |title=A Z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase. |journal=Proceedings of the National Academy of Sciences |volume=94 |issue=16 |pages=8421–8426 |pmid=9237992 |pmc=22942 |doi=10.1073/pnas.94.16.8421 |bibcode=1997PNAS...94.8421H|doi-access=free }}</ref> [[Crystallography|Crystallographic]] and [[nuclear magnetic resonance|NMR]] studies confirmed the biochemical findings that this domain bound Z-DNA in a non-sequence-specific manner.<ref name="Herbert1998">{{cite journal|last1=Herbert |first1=A. |last2=Schade |first2=M. |last3=Lowenhaupt |first3=K. |last4=Alfken |first4=J |last5=Schwartz |first5=T. |last6=Shlyakhtenko |first6=L. S. |last7=Lyubchenko |first7=Y. L. |last8=Rich |first8=A. |year=1998 |title=The Zα domain from human ADAR1 binds to the Z-DNA conformer of many different sequences |journal=Nucleic Acids Research |volume=26 |issue=15 |pages=2669–2672 |pmid=9671809 |pmc=147729 |doi=10.1093/nar/26.15.3486}}</ref><ref name="Schwartz1999">{{cite journal |last1=Schwartz |first1=T. |last2=Rould |first2=M. A. |last3=Lowenhaupt |first3=K. |last4=Herbert |first4=A. |last5=Rich |first5=A. |year=1999 |title=Crystal structure of the Zα domain of the human editing enzyme ADAR1 bound to left-handed Z-DNA |journal=Science |volume=284 |issue=5421 |pages=1841–1845 |pmid=10364558 |doi=10.1126/science.284.5421.1841}}</ref><ref name="Schade1999">{{cite journal|last1=Schade |first1=M. |last2=Turner |first2=C. J. |last3=Kühne |first3=R. |last4=Schmieder |first4=P. |last5=Lowenhaupt |first5=K. |last6=Herbert |first6=A. |last7=Rich |first7=A. |last8=Oschkinat |first8=H |year=1999 |title=The solution structure of the Zα domain of the human RNA editing enzyme ADAR1 reveals a prepositioned binding surface for Z-DNA |journal=Proceedings of the National Academy of Sciences |volume=96 |issue=22 |pages=2465–2470 |pmid=10535945 |pmc=22950 |doi=10.1073/pnas.96.22.12465 |bibcode=1999PNAS...9612465S|doi-access=free }}</ref> Related domains were identified in a number of other proteins through [[sequence homology]].<ref name="Herbert1997" /> The identification of the Zα domain provided a tool for other crystallographic studies that lead to the characterization of Z-RNA and the B–Z junction. Biological studies suggested that the Z-DNA binding domain of ADAR1 may localize this enzyme that modifies the sequence of the newly formed RNA to sites of active transcription.<ref name="Herbert2001">{{cite journal|last1=Herbert |first1=A. |last2=Rich |first2=A. |year=2001 |title=The role of binding domains for dsRNA and Z-DNA in the ''in vivo'' editing of minimal substrates by ADAR1 |journal=Proceedings of the National Academy of Sciences |volume=98 |issue=21 |pages=12132–12137 |pmid=11593027 |doi=10.1073/pnas.211419898 |bibcode=2001PNAS...9812132H |pmc=59780|doi-access=free }}</ref><ref name="Halber1999">{{cite web |title=Scientists observe biological activities of 'left-handed' DNA  |last=Halber |first=D. |date=1999-09-11 |publisher=MIT News Office |url=http://web.mit.edu/newsoffice/1999/zdna-0911.html |access-date=2008-09-29}}</ref> A role for Zα, Z-DNA and Z-RNA in defense of the genome against the invasion of Alu retro-elements in humans has evolved into a mechanism for the regulation of innate immune responses to dsRNA. Mutations in Zα are causal for human interferonopathies such as the Mendelian Aicardi-Goutières Syndrome.<ref name="Herbert2019">{{cite journal |last1=Herbert |first1=A. |year=2019 |title= Z-DNA and Z-RNA in human disease|journal=Communications Biology |volume=2  |page=7 |doi=10.1038/s42003-018-0237-x|pmid=30729177 |pmc=6323056 }}</ref><ref name="Herbert 2019 114–117"/>Additionally, Zα domains are demonstrated to localize at the stress granules because of their innate ability in binding nucleic acid. Furthermore, different Zα domains bind to the Z conformation of nucleic acid differently providing important avenues for specific targeting in drug discovery.

=== Consequences of Z-DNA binding to vaccinia E3L protein ===
As Z-DNA has been researched more thoroughly, it has been discovered that the structure of Z-DNA can bind to Z-DNA binding proteins through [[Van der Waals force|van der Waal forces]] and [[hydrogen bonding]].<ref name=":1" /> One example of a Z-DNA binding protein is the [[vaccinia]] E3L protein, which is a product of the E3L gene and mimics a mammalian protein that binds Z-DNA.<ref name=":4">{{Cite journal|last1=Kim|first1=Y.-G.|last2=Muralinath|first2=M.|last3=Brandt|first3=T.|last4=Pearcy|first4=M.|last5=Hauns|first5=K.|last6=Lowenhaupt|first6=K.|last7=Jacobs|first7=B. L.|last8=Rich|first8=A.|date=2003-05-30|title=A role for Z-DNA binding in vaccinia virus pathogenesis|journal=Proceedings of the National Academy of Sciences|volume=100|issue=12|pages=6974–6979|doi=10.1073/pnas.0431131100|pmid=12777633|issn=0027-8424|pmc=165815|bibcode=2003PNAS..100.6974K |doi-access=free}}</ref><ref>{{Cite journal|last1=Kim|first1=Y.-G.|last2=Lowenhaupt|first2=K.|last3=Oh|first3=D.-B.|last4=Kim|first4=K. K.|last5=Rich|first5=A.|date=2004-02-02|title=Evidence that vaccinia virulence factor E3L binds to Z-DNA in vivo: Implications for development of a therapy for poxvirus infection|journal=Proceedings of the National Academy of Sciences|volume=101|issue=6|pages=1514–1518|doi=10.1073/pnas.0308260100|issn=0027-8424|pmid=14757814|pmc=341766|bibcode=2004PNAS..101.1514K |doi-access=free}}</ref> Not only does the E3L protein have affinity to Z-DNA, it has also been found to play a role in the level of severity of virulence in mice caused by vaccinia virus, a type of [[poxvirus]]. Two critical components to the E3L protein that determine virulence are the [[N-terminus]] and the [[C-terminus]]. The N-terminus is made of up a sequence similar to that of the Zα domain, also called [[Adenosine deaminase z-alpha domain]], while the C-terminus is composed of a double stranded RNA binding motif.<ref name=":4" /> Through research done by Kim, Y. et al. at the Massachusetts Institute of Technology, it was shown that replacing the N-terminus of the E3L protein with a Zα domain sequence, containing 14 Z-DNA binding residues similar to E3L, had little to no effect on pathogenicity of the virus in mice.<ref name=":4" /> In Contrast, Kim, Y. et al. also found that deleting all 83 residues of the E3L N-terminus resulted in decreased virulence. This supports their claim that the N-terminus containing the Z-DNA binding residues is necessary for virulence.<ref name=":4" /> Overall, these findings show that the similar Z-DNA binding residues within the N-terminus of the E3L protein and the Zα domain are the most important structural factors determining virulence caused by the vaccinia virus, while amino acid residues not involved in Z-DNA binding have little to no effect. A future implication of these findings includes reducing Z-DNA binding of E3L in vaccines containing the vaccinia virus so negative reactions to the virus can be minimized in humans.<ref name=":4" />

Furthermore, Alexander Rich and Jin-Ah Kwon found that E3L acts as a [[transactivator]] for human IL-6, NF-AT, and p53 genes. Their results show that [[HeLa]] cells containing E3L had increased expression of human IL-6, NF-AT, and p53 genes and point mutations or deletions of certain Z-DNA binding amino acid residues decreased that expression.<ref name=":1">{{Cite journal|last1=Kwon|first1=J.-A.|last2=Rich|first2=A.|date=2005-08-26|title=Biological function of the vaccinia virus Z-DNA-binding protein E3L: Gene transactivation and antiapoptotic activity in HeLa cells|journal=Proceedings of the National Academy of Sciences|volume=102|issue=36|pages=12759–12764|doi=10.1073/pnas.0506011102|pmid=16126896|pmc=1200295|bibcode=2005PNAS..10212759K |issn=0027-8424|doi-access=free}}</ref> Specifically, mutations in Tyr 48 and Pro 63 were found to reduce transactivation of the previously mentioned genes, as a result of loss of hydrogen bonding and london dispersion forces between E3L and the Z-DNA.<ref name=":1" /> Overall, these results show that decreasing the bonds and interactions between Z-DNA and Z-DNA binding proteins decreases both virulence and gene expression, hence showing the importance of having bonds between Z-DNA and the E3L binding protein.

==Comparison geometries of some DNA forms==
[[Image:A-DNA, B-DNA and Z-DNA.png|right|thumb|Side view of A-, B-, and Z-DNA.]]
[[Image:B&Z&A DNA formula.svg|thumb|right|250px|The helix axis of A-, B-, and Z-DNA.]]
{| class="wikitable"
|+Geometry attributes of A-, B, and Z-DNA<ref name="Sinden1994">{{cite book|title=DNA Structure and Function |last=Sinden |first=Richard R. |date=1994 |publisher=Academic Press |edition=1st |isbn=978-0-126-45750-6 |page=398}}</ref><ref name="Rich1984">{{cite journal |last1=Rich |first1=A. |last2=Norheim |first2=A. |last3=Wang |first3=A. H. |title=The chemistry and biology of left-handed Z-DNA |journal=Annual Review of Biochemistry |volume=53 |issue=1 |pages=791–846 |year=1984 
|doi=10.1146/annurev.bi.53.070184.004043 |pmid=6383204}}</ref><ref name="pmid7937803">{{cite journal |doi=10.1073/pnas.91.20.9549 |last=Ho |first=P. S. |title=The non-B-DNA structure of d(CA/TG)<sub>''n''</sub> does not differ from that of Z-DNA |journal=Proceedings of the National Academy of Sciences |date=1994-09-27 |volume=91 |issue=20 |pages=9549–9553 |pmid=7937803 |pmc=44850|bibcode = 1994PNAS...91.9549H |doi-access=free }}</ref>
|-
!
!A-form
!B-form
!Z-form
|-
|Helix sense ||align="center"| right-handed ||align="center"| right-handed ||align="center"| left-handed
|-
|Repeating unit ||align="right"| 1 bp ||align="right"| 1 bp ||align="right"| 2 bp
|-
|Rotation/bp ||align="right"| 32.7° ||align="right"| 34.3° ||align="right"| 30°
|-
|bp/turn ||align="right"| 11 ||align="right"| 10 ||align="right"| 12
|-
|Inclination of bp to axis ||align="right"| +19° ||align="right"| −1.2° ||align="right"| −9°
|-
|Rise/bp along axis ||align="right"| 2.3 Å (0.23&nbsp;nm)||align="right"| 3.32 Å (0.332&nbsp;nm)||align="right"| 3.8 Å (0.38&nbsp;nm)
|-
|Pitch/turn of helix ||align="right"| 28.2 Å (2.82&nbsp;nm)||align="right"| 33.2 Å (3.32&nbsp;nm)||align="right"| 45.6 Å (4.56&nbsp;nm)
|-
|Mean propeller twist ||align="right"| +18° ||align="right"| +16° ||align="right"| 0°
|-
|[[Glycosyl angle]] ||align="center"| ''anti'' ||align="center"| ''anti'' ||align="center"| C: ''anti'',<br /> G: ''syn'' 
|-
|[[Sugar pucker]] ||align="center"| C3′-''endo'' ||align="center"| C2′-''endo'' ||align="center"| C: C2′-''endo'',<br />G: C3′-''endo''
|-
|Diameter ||align="right"| 23 Å (2.3&nbsp;nm)||align="right"| 20 Å (2.0&nbsp;nm)||align="right"| 18 Å (1.8&nbsp;nm)
|}

==See also==
{{Div col|colwidth=20em}}
*[[ADAR|ADAR1]]
*[[DNA supercoil]]
*[[Vaccinia|E3L]]
*[[Mechanical properties of DNA]]
*{{Proteopedia|Z-DNA}}
*[[Satellite DNA]]
*[[ZBP1|Z-DNA binding protein 1]] (ZBP1)
*[[Zuotin]]
{{div col end}}

==References==
{{reflist|30em}}

{{Nucleic acids}}

[[Category:DNA]]