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Z-DNA in the genome: from structure to disease

Abstract

The scope of studies investigating the architecture of genomic DNA has progressed steadily since the elucidation of the structure of B-DNA. In recent years, several non-canonical DNA structures including Z-DNA, G-quadruplexes, H-DNA, cruciform DNA, and i-motifs have been reported to form in genomic DNA and are closely related to the evolution and development of disease. The ability of these structures to form in genomic DNA indicates that they might have important cellular roles and are therefore retained during evolution. Understanding the impact of the formation of these secondary structures on cellular processes can enable identification of new targets for therapeutics. In this review, we report the state of understanding of Z-DNA structure and formation and their implication in disease. Finally, we state our perspective on the potential of Z-DNA as a therapeutic target.

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References

  • Allinquant B, Malfoy B, Schuller E and Leng M (1984) Presence of Z-DNA specific antibodies in Crohn disease polyradiculoneuritis and amyotrophic lateral sclerosis.pdf. Clin Exp Immunol 58: 29–36

  • Athanasiadis A (2012) Zalpha-domains: at the intersection between RNA editing and innate immunity. Seminars in cell & developmental biology 23: 275–280

  • Bayele HK, Peyssonnaux C, Giatromanolaki A, Arrais-Silva WW, Mohamed HS, Collins H, Giorgio S, Koukourakis M, Johnson RS, Blackwell JM, Nizet V, Srai SKS (2007) HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA forming microsatellite. Blood 110:3039–3048

    CAS  Article  Google Scholar 

  • Blaho JA, Wells RD (1989) Left-handed Z-DNA and genetic recombination. Prog Nucleic Acid Res Mol Biol 37:107–126

    CAS  Article  Google Scholar 

  • Bothe JR, Lowenhaupt K, Al-Hashimi HM (2012) Incorporation of CC steps into Z-DNA: interplay between B-Z junction and Z-DNA helical formation. Biochemistry 51(34):6871–6879

    CAS  Article  Google Scholar 

  • Edwards SF, Sirito M, Krahe R, Sinden RR (2009) A Z-DNA sequence reduces slipped-strand structure formation in the myotonic dystrophy type 2 (CCTG) x (CAGG) repeat. Proc Natl Acad Sci U S A 106:3270–3275

    CAS  Article  Google Scholar 

  • Ellison MJ, Feigon J, Kelleher RJ 3rd, Wang AH, Habener JF, Rich A (1986) An assessment of the Z-DNA forming potential of alternating dA-dT stretches in supercoiled plasmids. Biochemistry 25(12):3648–3655

    CAS  Article  Google Scholar 

  • Fuertes MA, Cepeda V, Alonso C, Pérez JM (2006) Molecular mechanisms for the B−Z transition in the example of poly[d(G−C)·d(G−C)] polymers. A critical review. Chem Rev 106:2045–2064

    CAS  Article  Google Scholar 

  • Ha SC, Choi J, Hwang HY, Rich A, Kim YG, Kim KK (2009) The structures of non-CG-repeat Z-DNAs co-crystallized with the Z-DNA-binding domain, hZ alpha(ADAR1). Nucleic Acids Res 37(2):629–637

    CAS  Article  Google Scholar 

  • Ha SC, Kim D, Hwang HY, Rich A, Kim YG, Kim KK (2008) The crystal structure of the second Z-DNA binding domain of human DAI (ZBP1) in complex with Z-DNA reveals an unusual binding mode to Z-DNA. Proc Natl Acad Sci U S A 105(52):20671–20676

    CAS  Article  Google Scholar 

  • Ha SC, Lokanath NK, Van Quyen D, Wu CA, Lowenhaupt K, Rich A, Kim YG, Kim KK (2004) A poxvirus protein forms a complex with left-handed Z-DNA: crystal structure of a Yatapoxvirus Zalpha bound to DNA. Proc Natl Acad Sci U S A 101(40):14367–14372

    CAS  Article  Google Scholar 

  • Ha SC, Lowenhaupt K, Rich A, Kim YG, Kim KK (2005) Crystal structure of a junction between B-DNA and Z-DNA reveals two extruded bases. Nature 437(7062):1183–1186

    CAS  Article  Google Scholar 

  • Herbert A (2019) Z-DNA and Z-RNA in human disease. Commun Biol 2:7

    Article  Google Scholar 

  • Ho PS, Ellison MJ, Quigley GJ, Rich A (1986) A computer aided thermodynamic approach for predicting the formation of Z-DNA in naturally occurring sequences. EMBO J 5(10):2737–2744

    CAS  Article  Google Scholar 

  • Khan N, Kolimi N, Rathinavelan T (2015) Twisting right to left: a…a mismatch in a CAG trinucleotide repeat overexpansion provokes left-handed Z-DNA conformation. PLoS Comput Biol 11(4):e1004162

    Article  Google Scholar 

  • Kim D, Hur J, Han JH, Ha SC, Shin D, Lee S, Park S, Sugiyama H, Kim KK (2018) Sequence preference and structural heterogeneity of BZ junctions. Nucleic Acids Res 46(19):10504–10513

    CAS  Article  Google Scholar 

  • Kim D, Hur J, Park K, Bae S, Shin D, Ha SC, Hwang HY, Hohng S, Lee JH, Lee S, Kim YG, Kim KK (2014) Distinct Z-DNA binding mode of a PKR-like protein kinase containing a Z-DNA binding domain (PKZ). Nucleic Acids Res 42(9):5937–5948

    CAS  Article  Google Scholar 

  • Kim K, Khayrutdinov BI, Lee CK, Cheong HK, Kang SW, Park H, Lee S, Kim YG, Jee J, Rich A, Kim KK, Jeon YH (2011) Solution structure of the Zbeta domain of human DNA-dependent activator of IFN-regulatory factors and its binding modes to B- and Z-DNAs. Proc Natl Acad Sci U S A 108(17):6921–6926

    CAS  Article  Google Scholar 

  • Lafer EM, Valle RP, Moller A, Nordheim A, Schur PH, Rich A, Stollar BD (1983) Z-DNA-specific antibodies in human systemic lupus erythematosus. J Clin Invest 71:314–321

    CAS  Article  Google Scholar 

  • Liu H, Mulholland N, Fu H, Zhao K (2006) Cooperative activity of BRG1 and Z-DNA formation in chromatin remodeling. Mol Cell Biol 26(7):2550–2559

    CAS  Article  Google Scholar 

  • Maruyama A, Mimura J, Harada N, Itoh K (2013) Nrf2 activation is associated with Z-DNA formation in the human HO-1 promoter. Nucleic Acids Res 41:5223–5234

    CAS  Article  Google Scholar 

  • McLean MJ, Blaho JA, Kilpatrick MW, Wells RD (1986) Consecutive a X T pairs can adopt a left-handed DNA structure. Proc Natl Acad Sci 83(16):5884–5888

    CAS  Article  Google Scholar 

  • Mulholland N, Xu Y, Sugiyama H, Zhao K (2012) SWI/SNF-mediated chromatin remodeling induces Z-DNA formation on a nucleosome. Cell Biosci 2:3

    CAS  Article  Google Scholar 

  • Peck LJ, Wang JC (1985) Transcriptional block caused by a negative supercoiling induced structural change in an alternating CG sequence. Cell 40(1):129–137

    CAS  Article  Google Scholar 

  • Pham HT, Park MY, Kim KK, Kim YG, Ahn JH (2006) Intracellular localization of human ZBP1: differential regulation by the Z-DNA binding domain, Zalpha, in splice variants. Biochem Biophys Res Commun 348(1):145–152

    CAS  Article  Google Scholar 

  • Ray BK, Dhar S, Shakya A, Ray A (2011) Z-DNA-forming silencer in the first exon regulates human ADAM-12 gene expression. Proc Natl Acad Sci 108:103–108

    CAS  Article  Google Scholar 

  • Renciuk D, Kypr J, Vorlícková M, Renčiuk D, Vorlíčková M (2010) CGG repeats associated with fragile X chromosome form left-handed Z-DNA structure. Biopolymers 95:174–181

    Article  Google Scholar 

  • Shin SI, Ham S, Park J, Seo SH, Lim CH, Jeon H, Huh J, Roh TY (2016) Z-DNA-forming sites identified by ChIP-Seq are associated with actively transcribed regions in the human genome. DNA Res

  • Subramani VK, Ravichandran S, Bansal V, Kim KK (2019) Chemical-induced formation of BZ-junction with base extrusion. Biochem Biophys Res Commun 508(4):1215–1220

    CAS  Article  Google Scholar 

  • Suram A, Rao KSJ, Latha KS, Viswamitra MA (2002) First evidence to show the topological change of DNA from B-dNA to Z-DNA conformation in the hippocampus of Alzheimer's brain. NeuroMolecular Med 2:289–297

    CAS  Article  Google Scholar 

  • Vorlíčková M, Kejnovská I, Tumová M, Kypr J (2001) Conformational properties of DNA fragments containing GAC trinucleotide repeats associated with skeletal displasias. Eur Biophys J 30:179–185

    Article  Google Scholar 

  • Wahls WP, Wallace LJ, Moore PD (1990) The Z-DNA motif d(TG)30 promotes reception of information during gene conversion events while stimulating homologous recombination in human cells in culture. Mol Cell Biol 10:785–793

    CAS  Article  Google Scholar 

  • Wang AHJ, Hakoshima T, van der Marel G, van Boom JH, Rich A (1984) AT base pairs are less stable than GC base pairs in Z-DNA: the crystal structure of d(m5CGTAm5CG). Cell 37:321–331

    CAS  Article  Google Scholar 

  • Wang AHJ, Quigley GJ, Kolpak FJ, Crawford JL, van Boom JH, van der Marel G, Rich A (1979) Molecular structure of a left-handed double helical DNA fragment at atomic resolution. Nature 282(5740):680–686

    CAS  Article  Google Scholar 

  • Wang G, Christensen LA, Vasquez KM (2006) Z-DNA-forming sequences generate large-scale deletions in mammalian cells. Proc Natl Acad Sci U S A 103(8):2677–2682

    CAS  Article  Google Scholar 

  • Wang G, Vasquez KM (2007) Z-DNA, an active element in the genome. Front Biosci 12:4424–4438

    CAS  Article  Google Scholar 

  • Wittig B, Wölfl S, Dorbic T, Vahrson W (1992) Transcription of human c-myc in permeabilized nuclei is associated with formation of Z-DNA in three discrete regions of the gene. EMBO J 11:4653–4663

    CAS  Article  Google Scholar 

  • Wolfl S, Martinez C, Rich A, Majzoub JA (1996) Transcription of the human corticotropin-releasing hormone gene in NPLC cells is correlated with Z-DNA formation. Proc Natl Acad Sci 93:3664–3668

    CAS  Article  Google Scholar 

  • Xu Y, Ikeda R, Sugiyama H (2003) 8-Methylguanosine: a powerful Z-DNA stabilizer. J Am Chem Soc 125:13519–13524

    CAS  Article  Google Scholar 

  • Zhang F, Huang Q, Yan J, Chen Z (2016) Histone acetylation induced transformation of B-DNA to Z-DNA in cells probed through FT-IR spectroscopy. Anal Chem 88:4179–4182

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the Samsung Science & Technology Foundation (SSTF-BA1301-01).

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Correspondence to Kyeong Kyu Kim.

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Subramaniyam Ravichandran declares that he has no conflict of interest. Vinod Kumar Subramani declares that he has no conflict of interest. Kyeong Kyu Kim declares that he has no conflict of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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This article is part of a Special Issue dedicated to the ‘2018 Joint Conference of the Asian Biophysics Association and Australian Society for Biophysics’ edited by Kuniaki Nagayama, Raymond Norton, Kyeong Kyu Kim, Hiroyuki Noji, Till Böcking, and Andrew Battle

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Ravichandran, S., Subramani, V.K. & Kim, K.K. Z-DNA in the genome: from structure to disease. Biophys Rev 11, 383–387 (2019). https://doi.org/10.1007/s12551-019-00534-1

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  • DOI: https://doi.org/10.1007/s12551-019-00534-1

Keywords

  • Z-DNA
  • Disease
  • Z-DNA-binding protein
  • Therapeutic target
  • Transcription