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The Biology of Left-handedZ-DNA*

Alan Herbert and Alexander Rich

From the Department of Biology,Massachusetts Institute of Technology,Cambridge, Massachusetts 02139

DNA encodes biological information in at least two differentways. First, through the linear order of nucleotides, it specifiesthe composition of proteins. Second, through its shape, DNAcan provide information that is used directly or indirectly by avariety of macromolecules to regulate the assembly of cellularmachines. DNA is capable of assuming many shapes (1). One ofthe most dramatic changes in shape is that which occurs ingoing from the familiar right-handed B-DNA double helix tothe slightly thinner and elongated left-handed Z-DNA confor-mation (2). This conformational change occurs most readily insegments with specialized sequences, favored largely by alter-nations of purines and pyrimidines, especially alternating de-oxycytidine and deoxyguanosine residues (3–5). A requirementfor specialized nucleotide sequences also appears to be true forother unusual DNA structures such as the TATA box, whichundergoes a major distortion in shape when bound by theTATA binding protein (6, 7).The biological role of non-B-DNA structures is an area of

active study. The aim of these investigations is to determinewhich alternate DNA conformations exist in vivo, how theirformation is regulated, and what information they convey.Here we will review recent studies that bear on the role ofZ-DNA in biologic systems.

Formation of Z-DNA in VitroThe existence of Z-DNA was first suggested by optical stud-

ies demonstrating that a polymer of alternating deox-yguanosine and deoxycytidine residues (d(CG)n) produced anearly inverted circular dichroism spectrum in a high saltsolution (8). The physical reason for this finding remained amystery until an atomic resolution crystallographic study ofd(CG)3 revealed a left-handed double helix, which maintainedWatson-Crick base pairing (2). The Z-DNA helix is built from adinucleotide repeat with the deoxycytidines in the anti confor-mation while deoxyguanosines are in the unusual syn form. InZ-DNA, there is a single narrow groove that corresponds to theminor groove of B-DNA. There is no major groove. Instead, the“information”-rich residues that allow sequence-specific recog-nition of B-DNA lie exposed on the convex outer surface ofZ-DNA (Fig. 1). The transition from B-DNA to Z-DNA involves“flipping” the base pairs upside down. During this process,deoxycytidine remains in the anti conformation because boththe sugar and base rotate, while only the base of deox-yguanosine inverts, moving it into the syn conformation. As aconsequence, the backbone follows a zigzag path, giving rise tothe name Z-DNA. Z-DNA can form from B-DNA under physi-ological salt conditions when deoxycytidine is 5-methylated (9).

The demonstration that Z-DNA formed under conditions ofnegative superhelical stress raised considerable excitement asthis brought the left-handed conformation within the realm ofbiology (3, 5, 10).Stabilization of Z-DNA by negative supercoiling illustrates a

number of features. First, Z-DNA is a higher energy conforma-tion than B-DNA and will only form when plasmids are tor-sionally stressed. The energy necessary to stabilize Z-DNA canbe determined by measuring the plasmid superhelical densityat which Z-DNA formation occurs, and it is proportional to thesquare of the number of negative supercoils (11–14). Second,sequences other than alternating purines and pyrimidines canform Z-DNA. The ease with which this occurs depends on thesequence; d(CG)n is best, d(TG)n is next, and a d(GGGC)nrepeat is better than d(TA)n (13, 15, 16). Third, formation ofB-Z DNA junctions, each of which has a free energy DG near 14kcal/mol, is a significant energetic barrier to Z-DNA formation(11).Based on these empirical findings, computer models have

been developed to rank the Z-DNA-forming potential of natu-rally occurring sequences (15, 17, 18). One analysis of 137 fullysequenced human genes demonstrated that sequences whichcould form Z-DNA easily were present in 98 and that they weredistributed nonrandomly throughout the gene; sequences were10 times more frequent in 59 than in 39 regions (17). This fitswith the expectation that the energy necessary to form Z-DNAin vivo is generated by transcription. As demonstrated by Liuand Wang (19), negative supercoils arise behind a moving RNApolymerase as it ploughs through the DNA double helix. Thetorsional strain generated by passage of RNA polymerases thenbecomes a potent source of energy to stabilize Z-DNA.

Z-DNA in Prokaryotic SystemsA number of experiments have been used to demonstrate

that Z-DNA can form in vivo. One approach uses chemicalmodification. Through use of either osmium tetroxide or potas-sium permanganate, it can be demonstrated that plasmidscontaining a d(CG)n insert will form Z-DNA in vivo (20, 21). UVcross-linking of bacteria treated with psoralens have confirmedthese results and made possible a precise measurement of theamount of unrestrained supercoiling present within Esche-richia coli (22). A more sophisticated approach has used aconstruct in which an EcoRI site is embedded in a Z-DNA-forming sequence (23–25). In the bacterial cell, this fragmentcan be methylated when it is in the B-DNA conformation, butit becomes resistant to methylation while in the Z-DNA confor-mation. Susceptibility to methylation thus can be used as ameasure of in vivo torsional strain. Results obtained with thissystem show that Z-DNA formation in E. coli occurs in theabsence of external perturbation and is regulated by transcrip-tion, an effect that is enhanced by mutations inactivating to-poisomerase I (24, 25). Formation of Z-DNA, however, was notobserved in Morganella, Klebsiella, or Enterobacter (25).

Z-DNA in Eukaryotic SystemsIt has been difficult to directly demonstrate the existence of

Z-DNA in eukaryotic systems. A number of early observationsclearly suggested its existence. Unlike B-DNA, Z-DNA is highlyimmunogenic, and polyclonal as well as monoclonal antibodiescan be made that recognize this conformation (26). The firstsuggestion that Z-DNA was found in eukaryotic systems came

* This minireview will be reprinted in the 1996 Minireview Compen-dium, which will be available in December, 1996. This work was fundedby grants from the National Institutes of Health, the Office for NavalResearch, and the National Science Foundation.

MinireviewTHE JOURNAL OF BIOLOGICAL CHEMISTRY

Vol. 271, No. 20, Issue of May 17, pp. 11595–11598, 1996© 1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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from work with humans. Analysis of sera obtained from pa-tients with autoimmune diseases, especially lupus erythema-tosis, showed that these patients produced antibodies whichwere highly specific for Z-DNA (27). These were produced dur-ing the exacerbations of the disease, together with antibodies tomany other nuclear components.Antibodies raised in rabbits and sheep were used in staining

experiments with both fixed (28) and unfixed polytene chromo-somes of Drosophila (29). These produced an unusual patternwith staining in the interband regions but not in the bands.Staining was especially intense in the puffs, which are associ-ated with high levels of transcriptional activity (reviewed inRef. 30). Antibodies were also used in staining ciliated protozoathat have both a macronucleus and a micronucleus (31). Themicronucleus is used for genetic reproduction, but the macro-nucleus is the site of all transcriptional activity. Here, again,the macronucleus stained exclusively, with no staining in themicronucleus. Both of these early experiments suggested some-what indirectly a link between transcriptional activity and thepresence of Z-DNA.Analysis of intact mammalian systems has been more com-

plicated. There are a number of limitations in these experi-ments. No phenotype has been associated with the presence orabsence of Z-DNA-forming sequences, thus limiting the use ofgenetic approaches. In addition, regulation of Z-DNA is likelyto be very complex. For example, what is the importance of thethree RNA polymerases relative to production of Z-DNA? It isknown that RNA polymerase I works on some favorable Z-DNA-forming sequences in ribosomal RNA genes. In addition,it is not known how the torsional strain in regions 59 to RNApolymerase II promoters is regulated. What is the influence ofthe TATA box sequence bound to its proteins? Are genes lack-ing a TATA box more topologically sensitive to the torsionalstrain generated by the moving polymerase? In this context,the effect of potential Z-DNA-forming sequences upstream of apromoter must be interpreted carefully; deletion or mutation ofsuch regions, as in the case of the SV40 enhancer which hasregions of alternating purine/pyrimidine repeats, may have

many different interpretations (32–35).A number of experiments have been carried out using met-

abolically active permeabilized mammalian nuclei, which wereformed by embedding intact cells in agarose using the methodof Jackson and Cook (36). Here, low concentrations of detergentare used to lyse the cytoplasmic membrane and permeabilizethe nuclear membrane. These nuclei have been shown to rep-licate DNA at 85% of the rate observed in the intact cell, andthey are active in transcription (37). In these experiments theamount of Z-DNA present in the gene is measured by diffusingbiotin-labeled anti-Z-DNA monoclonal antibodies into thebeads (38). The amount of Z-DNAwas measured initially by theamount of radioactive streptavidin that would bind within thenucleus. These experiments showed that, at low concentrationsof antibody, the amount of Z-DNA measured was independentof the antibody added over a 100-fold change in antibody con-centration. Furthermore, the amount of Z-DNA depended onDNA negative torsional strain. It increased dramatically astranscription increased but was largely unaffected by DNAreplication (39).It was found that individual genes could be assayed by cross-

linking the antibody to DNA using a 10-ns exposure of a laserat 266 nm (40). Release of DNA fragments with attached anti-body was accomplished by diffusing in restriction endonucle-ases and performing an in situ DNA digest. Following isolationof biotin-labeled antibody-DNA complexes with streptavidinmagnetobeads, free DNA was obtained by proteolysis. Theseexperiments made it possible to determine which regions of agene form Z-DNA. Using hybridization or polymerase chainreaction techniques, the c-myc gene was studied in murineU937 cells (40). Three transcription-dependent Z-DNA-formingsegments were identified in the 59 region of the gene with twoof them near promoters (Fig. 2) (41). Retinoic acid, which in-duces the cells to differentiate into macrophages, was thenused to down-regulate expression of c-myc. Loss of c-myc ex-pression was accompanied by a rapid reduction in the amountof Z-DNA present in these three regions. In contrast, Z-DNAwas detectable by polymerase chain reaction with probes forthe b-actin gene under all the conditions tested. b-Actin is notdown-regulated with differentiation.In other studies with a primary liver cell line, induction of

Z-DNA was measured in the corticotropin hormone-releasinggene (42). Z-DNA formation increased when the gene was up-

FIG. 1. The “information-rich” residues that allow sequence-specific recognition of the major groove of B-DNA lie on theconvex surface of left-handed Z-DNA helix. The two DNA strandsof each duplex are highlighted by solid black lines. The “zigzag” natureof the Z-DNA backbone is clearly seen.

FIG. 2. Z-DNA-forming segments, shown in red, can be de-tected in the genes encoding corticotropin-releasing hormone(crh) and the c-myc 67-kDa protein product. Z-DNA forms onlywhen these genes are transcriptionally active. The promoters for eachgene are labeled with an arrow and numbered according to their loca-tion within the gene. Translated regions of exons are shown in greenand untranslated parts in yellow. Introns are shown by a heavy blackline.

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regulated and decreased when it was down-regulated. Thisfinding suggests that physiological events are being measuredin these systems.A major conclusion from these studies is that Z-DNA forms

largely, if not exclusively, behind a moving RNA polymeraseand is stabilized by the negative supercoiling generated byDNA transcription.

Functional Consequences of Z-DNA FormationIn principle, Z-DNA formation could have a functional role

that need not involve recognition of its shape by proteins. It hasbeen shown that E. coli RNA polymerase does not transcribethrough Z-DNA (43). Thus, the formation of Z-DNA behind (59)a moving polymerase may block the following RNA polymerasefrom transcribing that region of a gene. This might ensurespatial separation between successive polymerases. As a con-sequence, processing of an RNA would then be physically andtemporally removed from that of subsequent transcripts, per-haps minimizing non-functional eukaryotic trans-splicing.Alternatively, formation of Z-DNA could facilitate recombi-

nation of homologous chromosomal domains by relieving topo-logical strain that arises when intact duplexes are intertwined(44). The Z-DNA-forming d(CA/GT)n sequence has been shownto be recombinogenic in yeast (45) but is found to be lessefficient than d(CG)n in human cells (46, 47). Furthermore,there have been several reports correlating chromosomalbreakpoints in human tumors to potential Z-DNA-forming se-quences, although no causal relationship has yet been estab-lished (48–52). Last, Z-DNA formation could affect the place-ment of nucleosomes as well as the organization ofchromosomal domains (53).Identification of proteins that bind to Z-DNA would indi-

rectly establish the presence of Z-DNA in vivo and help estab-lish a biological role for this shape. There has been an extensivesearch by a number of laboratories for Z-DNA binding proteins.Early studies were unfruitful and caused widespread skepti-cism that Z-DNA would be associated with any biological func-tion. Many of the positive results reported in these studies mayhave been due either to artifacts or misinterpretation of data(18, 54, 55). However, absence of proof was confused withabsence of existence.

A High Affinity Z-DNA Binding Protein withEnzymatic Activity

Recent results give cause for optimism. An assay that by itsdesign detects only proteins with high affinity for Z-DNA hasrevealed that one type of double-stranded RNA adenosinedeaminase (dsRAD)1 called DRADA binds Z-DNA in vitro (56–58). The dissociation constant of the Z-DNA binding domain isnanomolar, making it likely that this interaction is of biologicalrelevance. The domain maps to a region separate from thethree copies of the RNA binding motif present in the proteinand also from the catalytic domain (59–61).DRADA is an example of a family of deaminases, the dsRAD

family, that modify mRNA by catalyzing the hydrolytic deami-nation of adenine to inosine in regions that are double-stranded(62–65). RNA shape is important in this reaction as neithersingle-stranded RNA nor DNA are substrates for this reaction.The efficiency of editing in vitro is influenced by the length ofdsRNA, with maximum efficiency seen in a synthetic substrateabout 100 base pairs long (66). It is likely that different mem-bers of the dsRAD family will obtain specificity from the rec-ognition of different RNA shapes (67). Members of the dsRADfamily are ubiquitous in metazoa, suggesting that this activity

is of great evolutionary significance (59, 68, 69). These enzymesmay be an important source of phenotypic variation as theyhave the potential to significantly alter the linear flow of infor-mation from DNA to RNA (59). For example, inosine is trans-lated as guanine, so that editing of a codon can result in thesubstitution of one amino acid for another. An illustrativeexample of the type of reaction that a dsRAD may catalyze isediting of the GluR-B receptor; whether DRADA or anothermember of the dsRAD family, such as RED-1, is involved in thisreaction is currently a matter of debate (70). Editing of thesecond transmembrane domain of the GluR-B receptor RNAresults in the substitution of an arginine (CGG) for glutamine(CAG), changing the electrophysiological properties of the as-sembled receptor (71). The double-stranded RNA substratethat is modified by the enzyme is formed by folding the 39-intron back onto the exon to base pair with the site that isedited (72). In this case, the involvement of introns requiresthat editing occurs soon after transcription of RNA and beforesplicing.The potential involvement of introns in creating the sub-

strates for editing provides a number of rationales for therecognition of Z-DNA by DRADA. As discussed above, Z-DNAin vivo is a transcription-dependent structure and will formwhen appropriate sequences are present behind (59 to) a mov-ing RNA polymerase. This transcription-induced Z-DNA mayserve to localize DRADA to a particular region of a gene whereediting is to occur, and it may also prevent indiscriminateediting of other regions (Fig. 3). What is important is that theZ-DNA binding domain of the editing enzyme would target onlytranscribing genes and allow DRADA to act before the splicingapparatus removes the intron. In addition, recognition of Z-DNA by DRADA may block the gene from further transcriptionuntil editing of the RNA is complete. Currently there is nodirect evidence in vivo that the Z-DNA binding domain influ-ences the catalytic function of the enzyme. However, DRADA ispresent as a complex inside cells, and interactions may bemediated through other proteins. It should be possible to ex-amine the role of Z-DNA recognition by DRADA in vivo byusing UV cross-linking to identify the regions of genes that arebound to DRADA and correlate these with sites of dsRNAediting. It will also be of interest to determine whether othermembers of the dsRAD family are present within this complex.It is also possible that Z-DNA is not the only transcription-de-pendent structure recognized by this family of enzymes.

1 The abbreviation used is: dsRAD, double-stranded RNA adenosinedeaminase.

FIG. 3. In vivo, Z-DNA is thought to be stabilized by the nega-tive supercoiling generated by an RNA polymerase movingthrough a gene. Transcription also gives rise to regions of double-stranded RNA (dsRNA), formed when a nascent RNA transcript foldsback on itself. An RNA editing enzyme, dsRNA adenosine deaminase(DRADA), has been shown to bind both Z-DNA and dsRNA with nano-molar affinity. Each nucleic acid is bound by DRADA through a sepa-rate domain. This enzyme then catalyzes the hydrolytic deamination ofadenine within the dsRNA to form inosine. Inosine is subsequentlytranslated as guanine. Several editing sites may exist in a singlepre-mRNA. DRADA thus utilizes the structural information encoded byDNA and RNA shapes to change the message read from a gene.

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Other proteins may exist that bind to Z-DNA with loweraffinity than DRADA. It has been demonstrated that peptidesin which every second residue is lysine will stabilize Z-DNA invitro at micromolar concentrations (73). This provides a simpleprotein motif with which to recognize Z-DNA. This motif existsin a number of proteins, but it remains to be shown that suchproteins interact with Z-DNA. In addition, evidence has beenpresented to show that topoisomerase II from Drosophila, hu-mans, and calf thymus recognizes a number of different DNAshapes, including Z-DNA (74–76). However, the domain inter-acting with these shapes has not yet been biochemicallydefined.

Future ProspectsWhile a role for Z-DNA in vivo has not yet been firmly

established, the recognition of this shape by DRADA provides apromising lead. Currently there are many unresolved ques-tions. 1) How many of the potential Z-DNA-forming regions ina genome actually form Z-DNA in vivo? 2) Do some of theZ-DNA-forming regions represent sites of action of DRADA andare they recognized by other members of the dsRAD family? 3)What is the nature of the complex that includes DRADA andhow do the components interact? Is this complex an editosomecontaining other RNA editing enzymes? 4) Since DRADA has amodular structure, are there other proteins that have a Z-DNAbinding domain but a different enzymatic function? 5) Arethere other families of Z-DNA binding proteins? The answers tothese questions are of great interest and will lead to newinsights on how nucleic acid shape affects the linear flow ofinformation from DNA to RNA to protein.

Acknowledgment—We thank Dr. I. Berger for a careful reading of themanuscript.

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