Targeting G-quadruplexes in gene promoters: a novel anticancer strategy?

G-quadruplexes are four-stranded DNA structures that are over-represented in gene promoter regions and are viewed as emerging therapeutic targets in oncology, as transcriptional repression of oncogenes through stabilization of these structures could be a novel anticancer strategy. Many gene promoter G-quadruplexes have physicochemical properties and structural characteristics that might make them druggable, and their structural diversity suggests that a high degree of selectivity might be possible. Here, we describe the evidence for G-quadruplexes in gene promoters and discuss their potential as therapeutic targets, as well as progress in the development of strategies to harness this potential through intervention with small-molecule ligands.

[1]  Mitali Mukerji,et al.  Genome-wide prediction of G4 DNA as regulatory motifs: role in Escherichia coli global regulation. , 2006, Genome research.

[2]  Yan Xu,et al.  The new models of the human telomere d[AGGG(TTAGGG)3] in K+ solution. , 2006, Bioorganic & medicinal chemistry.

[3]  E. Maher,et al.  The Telomerase Antagonist, Imetelstat, Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth , 2010, Clinical Cancer Research.

[4]  M. Daras,et al.  Novel Checkpoint Response to Genotoxic Stress Mediated by Nucleolin-Replication Protein A Complex Formation , 2005, Molecular and Cellular Biology.

[5]  M. Teulade‐Fichou,et al.  A Hitchhiker′s Guide to G‐Quadruplex Ligands , 2008 .

[6]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[7]  Stella Pelengaris,et al.  c-MYC: more than just a matter of life and death , 2002, Nature Reviews Cancer.

[8]  A. Phan,et al.  Small-molecule interaction with a five-guanine-tract G-quadruplex structure from the human MYC promoter , 2005, Nature chemical biology.

[9]  Stephen Neidle,et al.  A conserved quadruplex motif located in a transcription activation site of the human c-kit oncogene. , 2006, Biochemistry.

[10]  A. Phan,et al.  Solution structures of all parallel-stranded monomeric and dimeric G-quadruplex scaffolds of the human c-kit2 promoter , 2010, Nucleic acids research.

[11]  Laurence H. Hurley,et al.  Structures, folding patterns, and functions of intramolecular DNA G-quadruplexes found in eukaryotic promoter regions. , 2008, Biochimie.

[12]  Stephen Neidle,et al.  Mechanism of acridine-based telomerase inhibition and telomere shortening. , 2007, Biochemical pharmacology.

[13]  Manikandan Paramasivam,et al.  The KRAS Promoter Responds to Myc-associated Zinc Finger and Poly(ADP-ribose) Polymerase 1 Proteins, Which Recognize a Critical Quadruplex-forming GA-element* , 2010, The Journal of Biological Chemistry.

[14]  Danzhou Yang,et al.  Structural insights into G-quadruplexes: towards new anticancer drugs. , 2010, Future medicinal chemistry.

[15]  Rashi Halder,et al.  Genome-wide analysis predicts DNA structural motifs as nucleosome exclusion signals. , 2009, Molecular bioSystems.

[16]  R. Memmott,et al.  A novel G-quadruplex-forming GGA repeat region in the c-myb promoter is a critical regulator of promoter activity , 2008, Nucleic acids research.

[17]  Yan Lin,et al.  Greglist: a database listing potential G-quadruplex regulated genes , 2007, Nucleic Acids Res..

[18]  K. Flaherty,et al.  Inhibition of mutated, activated BRAF in metastatic melanoma. , 2010, The New England journal of medicine.

[19]  S. Tavaré,et al.  Genome-wide analysis of a G-quadruplex-specific single-chain antibody that regulates gene expression , 2009, Nucleic acids research.

[20]  S. Balasubramanian,et al.  A novel small molecule that alters shelterin integrity and triggers a DNA-damage response at telomeres. , 2008, Journal of the American Chemical Society.

[21]  Yiqiang Zhao,et al.  Genome-wide analysis reveals regulatory role of G4 DNA in gene transcription. , 2008, Genome research.

[22]  G. Parkinson,et al.  Sequence occurrence and structural uniqueness of a G-quadruplex in the human c-kit promoter , 2007, Nucleic acids research.

[23]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[24]  A. Phan,et al.  Propeller-type parallel-stranded G-quadruplexes in the human c-myc promoter. , 2004, Journal of the American Chemical Society.

[25]  D. V. Von Hoff,et al.  Design and synthesis of fluoroquinophenoxazines that interact with human telomeric G-quadruplexes and their biological effects. , 2001, Molecular cancer therapeutics.

[26]  J. Fletcher,et al.  Targeting human gastrointestinal stromal tumor cells with a quadruplex-binding small molecule. , 2009, Journal of medicinal chemistry.

[27]  R. Eisenman,et al.  Myc's broad reach. , 2008, Genes & development.

[28]  W. Gilbert,et al.  Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis , 1988, Nature.

[29]  Manikandan Paramasivam,et al.  Structural polymorphism within a regulatory element of the human KRAS promoter: formation of G4-DNA recognized by nuclear proteins , 2008, Nucleic acids research.

[30]  F. Johnson,et al.  Genomic distribution and functional analyses of potential G-quadruplex-forming sequences in Saccharomyces cerevisiae , 2007, Nucleic acids research.

[31]  S. Cogoi,et al.  G-quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcription , 2006, Nucleic acids research.

[32]  Laurence H. Hurley,et al.  Facilitation of a structural transition in the polypurine/polypyrimidine tract within the proximal promoter region of the human VEGF gene by the presence of potassium and G-quadruplex-interactive agents , 2005, Nucleic acids research.

[33]  D. Ly,et al.  Loop and backbone modifications of peptide nucleic acid improve g-quadruplex binding selectivity. , 2009, Journal of the American Chemical Society.

[34]  A. D. Van den Abbeele,et al.  Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  J. Borowiec,et al.  Formation of a Complex between Nucleolin and Replication Protein a after Cell Stress Prevents Initiation of DNA Replication , 2000, The Journal of cell biology.

[36]  S. Neidle,et al.  The relationship of potential G-quadruplex sequences in cis-upstream regions of the human genome to SP1-binding elements , 2008, Nucleic acids research.

[37]  S. Neidle,et al.  Inhibition of human telomerase by a G-quadruplex-interactive compound. , 1997, Journal of medicinal chemistry.

[38]  S. Neidle,et al.  Highly prevalent putative quadruplex sequence motifs in human DNA , 2005, Nucleic acids research.

[39]  Imrich Géci,et al.  Identification of a new G-quadruplex motif in the KRAS promoter and design of pyrene-modified G4-decoys with antiproliferative activity in pancreatic cancer cells. , 2009, Journal of medicinal chemistry.

[40]  George Iliakis,et al.  Regulation of DNA Replication after Heat Shock by Replication Protein A-Nucleolin Interactions* , 2001, The Journal of Biological Chemistry.

[41]  Shantanu Chowdhury,et al.  QuadBase: genome-wide database of G4 DNA—occurrence and conservation in human, chimpanzee, mouse and rat promoters and 146 microbes , 2007, Nucleic Acids Res..

[42]  Roger A. Jones,et al.  Solution structure of the biologically relevant G-quadruplex element in the human c-MYC promoter. Implications for G-quadruplex stabilization. , 2005, Biochemistry.

[43]  Yoon-Joo Shin,et al.  Evidence of the formation of G-quadruplex structures in the promoter region of the human vascular endothelial growth factor gene , 2010, Nucleic acids research.

[44]  S. Balasubramanian,et al.  A G-rich sequence within the c-kit oncogene promoter forms a parallel G-quadruplex having asymmetric G-tetrad dynamics. , 2009, Journal of the American Chemical Society.

[45]  Shankar Balasubramanian,et al.  G-quadruplexes in promoters throughout the human genome , 2006, Nucleic acids research.

[46]  S. Balasubramanian,et al.  Single-molecule conformational analysis of G-quadruplex formation in the promoter DNA duplex of the proto-oncogene c-kit. , 2007, Journal of the American Chemical Society.

[47]  Lauren B. Murata,et al.  NM23-H2 may play an indirect role in transcriptional activation of c-myc gene expression but does not cleave the nuclease hypersensitive element III1 , 2009, Molecular Cancer Therapeutics.

[48]  A. Lane,et al.  Stability and kinetics of G-quadruplex structures , 2008, Nucleic acids research.

[49]  L. Hurley,et al.  The role of supercoiling in transcriptional control of MYC and its importance in molecular therapeutics , 2009, Nature Reviews Cancer.

[50]  Stephen Neidle,et al.  The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function. , 2005, Cancer research.

[51]  M. Groudine,et al.  Control of c-myc regulation in normal and neoplastic cells. , 1991, Advances in cancer research.

[52]  Han Min Wong,et al.  Stable G-quadruplexes are found outside nucleosome-bound regions. , 2009, Molecular bioSystems.

[53]  T. Simonsson,et al.  A nuclease hypersensitive element in the human c-myc promoter adopts several distinct i-tetraplex structures. , 2000, Biochemical and biophysical research communications.

[54]  M. Borgognone,et al.  Cellular nucleic-acid-binding protein, a transcriptional enhancer of c-Myc, promotes the formation of parallel G-quadruplexes. , 2010, The Biochemical journal.

[55]  K. Kohn,et al.  Cross-Linking : History and Prospects of DNA-targeted Cancer Treatment†” Fifteenth , 2006 .

[56]  Daekyu Sun,et al.  Evidence for the presence of a guanine quadruplex forming region within a polypurine tract of the hypoxia inducible factor 1alpha promoter. , 2005, Biochemistry.

[57]  Amy Lin,et al.  Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis. , 2009, Cancer research.

[58]  J. Shklover,et al.  Quadruplex structures of muscle gene promoter sequences enhance in vivo MyoD-dependent gene expression , 2010, Nucleic acids research.

[59]  A. Chan,et al.  Stabilization of G-quadruplex DNA and down-regulation of oncogene c-myc by quindoline derivatives. , 2007, Journal of medicinal chemistry.

[60]  K. Shin‐ya,et al.  Telomerase inhibition with a novel G-quadruplex-interactive agent, telomestatin: in vitro and in vivo studies in acute leukemia , 2006, Oncogene.

[61]  G. Parkinson,et al.  Topology conservation and loop flexibility in quadruplex-drug recognition: crystal structures of inter- and intramolecular telomeric DNA quadruplex-drug complexes. , 2008, Journal of molecular biology.

[62]  Margaret Gardiner-Garden,et al.  Identification of Functional Networks of Estrogen- and c-Myc-Responsive Genes and Their Relationship to Response to Tamoxifen Therapy in Breast Cancer , 2008, PloS one.

[63]  W. Foye,et al.  Foye's Principles of Medicinal Chemistry , 2002 .

[64]  Ming-Chih Crouthamel,et al.  Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors , 2009, British Journal of Cancer.

[65]  E. Gilson,et al.  Stabilization of quadruplex DNA perturbs telomere replication leading to the activation of an ATR-dependent ATM signaling pathway , 2009, Nucleic acids research.

[66]  H. Nakagama,et al.  Protein hnRNP A1 and its derivative Up1 unfold quadruplex DNA in the human KRAS promoter: implications for transcription , 2009, Nucleic acids research.

[67]  Sarah W. Burge,et al.  Structure of an unprecedented G-quadruplex scaffold in the human c-kit promoter. , 2007, Journal of the American Chemical Society.

[68]  Daekyu Sun,et al.  Identification and Characterization of Nucleolin as a c-myc G-quadruplex-binding Protein* , 2009, The Journal of Biological Chemistry.

[69]  Structural and functional characterizations of the G-quartet and i-motif elements in retinoblastoma susceptibility genes (Rb). , 2005, Nucleic acids symposium series.

[70]  Stephen Neidle,et al.  Structural basis of DNA quadruplex recognition by an acridine drug. , 2008, Journal of the American Chemical Society.

[71]  N. Maizels,et al.  Gene function correlates with potential for G4 DNA formation in the human genome , 2006, Nucleic acids research.

[72]  R. Sinden.  DNA Structure and Function , 1994 .

[73]  D. Biard,et al.  Role of ATM in the telomere response to the G-quadruplex ligand 360A , 2008, Nucleic acids research.

[74]  N. Maizels,et al.  Conserved elements with potential to form polymorphic G-quadruplex structures in the first intron of human genes , 2008, Nucleic acids research.

[75]  M. Fukayama,et al.  C‐kit Gene Abnormalities in Gastrointestinal Stromal Tumors (Tumors of Interstitial Cells of Cajal) , 1999, Japanese journal of cancer research : Gann.

[76]  Dinshaw J. Patel,et al.  Structure of the human telomere in K+ solution: an intramolecular (3 + 1) G-quadruplex scaffold. , 2006, Journal of the American Chemical Society.

[77]  L. Hurley,et al.  The dynamic character of the G-quadruplex element in the c-MYC promoter and modification by TMPyP4. , 2004, Journal of the American Chemical Society.

[78]  L. Hurley,et al.  Targeting MYC Expression through G-Quadruplexes. , 2010, Genes & cancer.

[79]  Shankar Balasubramanian,et al.  An RNA G-quadruplex in the 5' UTR of the NRAS proto-oncogene modulates translation. , 2007, Nature chemical biology.

[80]  A. Lane,et al.  Resolution and characterization of the structural polymorphism of a single quadruplex-forming sequence , 2010, Nucleic acids research.

[81]  K. Shin‐ya,et al.  Disabling c-Myc in Childhood Medulloblastoma and Atypical Teratoid/Rhabdoid Tumor Cells by the Potent G-Quadruplex Interactive Agent S2T1-6OTD , 2010, Molecular Cancer Therapeutics.

[82]  L. Boxer,et al.  The Transcription Factor, Nm23H2, Binds to and Activates the Translocated c-myc Allele in Burkitt's Lymphoma (*) , 1995, The Journal of Biological Chemistry.

[83]  M. Gregory,et al.  c-Myc Proteolysis by the Ubiquitin-Proteasome Pathway: Stabilization of c-Myc in Burkitt's Lymphoma Cells , 2000, Molecular and Cellular Biology.

[84]  S. Neidle,et al.  Biaryl polyamides as a new class of DNA quadruplex-binding ligands. , 2009, Chemical communications.

[85]  Shankar Balasubramanian,et al.  Prevalence of quadruplexes in the human genome , 2005, Nucleic acids research.

[86]  E. Postel,et al.  Nucleoside diphosphate kinase enzyme activity of NM23-H2/PuF is not required for its DNA binding and in vitro transcriptional functions. , 1994, The Journal of biological chemistry.

[87]  Roger A. Jones,et al.  NMR solution structure of the major G-quadruplex structure formed in the human BCL2 promoter region , 2006, Nucleic acids research.

[88]  L. Hurley,et al.  Characterization of the G-quadruplexes in the duplex nuclease hypersensitive element of the PDGF-A promoter and modulation of PDGF-A promoter activity by TMPyP4 , 2007, Nucleic acids research.

[89]  S. Balasubramanian,et al.  Trisubstituted isoalloxazines as a new class of G-quadruplex binding ligands: small molecule regulation of c-kit oncogene expression. , 2007, Journal of the American Chemical Society.

[90]  L. Hurley,et al.  Formation of a unique end-to-end stacked pair of G-quadruplexes in the hTERT core promoter with implications for inhibition of telomerase by G-quadruplex-interactive ligands. , 2009, Journal of the American Chemical Society.

[91]  T. Duka,et al.  First evidence of a functional interaction between DNA quadruplexes and poly(ADP-ribose) polymerase-1. , 2008, ACS chemical biology.

[92]  T. Haneji,et al.  Cleavage of nucleolin and AgNOR proteins during apoptosis induced by anticancer drugs in human salivary gland cells. , 2005, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[93]  A. Ullrich,et al.  Human proto‐oncogene c‐kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. , 1987, The EMBO journal.

[94]  Stephen Neidle,et al.  The structures of quadruplex nucleic acids and their drug complexes. , 2009, Current opinion in structural biology.

[95]  L. Hurley,et al.  The role of G-quadruplex/i-motif secondary structures as cis-acting regulatory elements , 2010, Pure and applied chemistry. Chimie pure et appliquee.

[96]  S. J. Flint,et al.  Human c-myc transcription factor PuF identified as nm23-H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis. , 1993, Science.

[97]  Oleg Kikin,et al.  QGRS Mapper: a web-based server for predicting G-quadruplexes in nucleotide sequences , 2006, Nucleic Acids Res..

[98]  M. Katahira,et al.  An intramolecular quadruplex of (GGA)(4) triplet repeat DNA with a G:G:G:G tetrad and a G(:A):G(:A):G(:A):G heptad, and its dimeric interaction. , 2001, Journal of molecular biology.

[99]  Stephen Neidle,et al.  Putative DNA quadruplex formation within the human c-kit oncogene. , 2005, Journal of the American Chemical Society.

[100]  L. Hurley,et al.  The c-MYC NHE III(1): function and regulation. , 2010, Annual review of pharmacology and toxicology.

[101]  S. Dimitrov,et al.  Functions of the histone chaperone nucleolin in diseases. , 2007, Sub-cellular biochemistry.

[102]  Aaron Klug,et al.  Telomeric DNA dimerizes by formation of guanine tetrads between hairpin loops , 1989, Nature.

[103]  Y-X Zeng,et al.  Inhibition of myc promoter and telomerase activity and induction of delayed apoptosis by SYUIQ-5, a novel G-quadruplex interactive agent in leukemia cells , 2007, Leukemia.

[104]  J. Borowiec,et al.  Stress-Dependent Nucleolin Mobilization Mediated by p53-Nucleolin Complex Formation , 2002, Molecular and Cellular Biology.

[105]  R. Deng,et al.  G-quadruplex ligand SYUIQ-5 induces autophagy by telomere damage and TRF2 delocalization in cancer cells , 2009, Molecular Cancer Therapeutics.

[106]  Charles A Laughton,et al.  Pharmacodynamics of the G-Quadruplex-Stabilizing Telomerase Inhibitor 3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) in Vitro: Activity in Human Tumor Cells Correlates with Telomere Length and Can Be Enhanced, or Antagonized, with Cytotoxic Agents , 2005, Molecular Pharmacology.

[107]  Roger A. Jones,et al.  Human telomeric sequence forms a hybrid-type intramolecular G-quadruplex structure with mixed parallel/antiparallel strands in potassium solution , 2006, Nucleic acids research.

[108]  Stephen Neidle,et al.  Crystal structure of parallel quadruplexes from human telomeric DNA , 2002, Nature.

[109]  Stephen Neidle,et al.  Human telomeric G‐quadruplex: The current status of telomeric G‐quadruplexes as therapeutic targets in human cancer , 2010, The FEBS journal.

[110]  Carlo Leonetti,et al.  Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect. , 2007, The Journal of clinical investigation.

[111]  D. Levens,et al.  The functional response of upstream DNA to dynamic supercoiling in vivo , 2008, Nature Structural &Molecular Biology.

[112]  Yan Xu,et al.  Formation of the G-quadruplex and i-motif structures in retinoblastoma susceptibility genes (Rb) , 2006, Nucleic acids research.

[113]  E. Gilson,et al.  PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy , 2010, Oncogene.

[114]  C. Leung,et al.  Structure-based design of platinum(II) complexes as c-myc oncogene down-regulators and luminescent probes for G-quadruplex DNA. , 2010, Chemistry.

[115]  Hyun-Jin Kang,et al.  Novel molecular mechanism for actinomycin D activity as an oncogenic promoter G-quadruplex binder. , 2009, Biochemistry.

[116]  L. Hurley,et al.  Deconvoluting the structural and drug-recognition complexity of the G-quadruplex-forming region upstream of the bcl-2 P1 promoter. , 2006, Journal of the American Chemical Society.

[117]  Ram Krishna Thakur,et al.  Genome-wide computational and expression analyses reveal G-quadruplex DNA motifs as conserved cis-regulatory elements in human and related species. , 2008, Journal of medicinal chemistry.

[118]  G. Krystal,et al.  Selective Sp1 binding is critical for maximal activity of the human c-kit promoter. , 1998, Blood.

[119]  David M. Prescott,et al.  Inhibition of telomerase by G-quartet DMA structures , 1991, Nature.

[120]  K. Lindblad-Toh,et al.  Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals , 2005, Nature.

[121]  Ram Krishna Thakur,et al.  Metastases suppressor NM23-H2 interaction with G-quadruplex DNA within c-MYC promoter nuclease hypersensitive element induces c-MYC expression , 2008, Nucleic acids research.

[122]  S. Balasubramanian,et al.  G-quadruplex-binding benzo[a]phenoxazines down-regulate c-KIT expression in human gastric carcinoma cells. , 2011, Journal of the American Chemical Society.

[123]  A. Saxena,et al.  Nucleolin inhibits Hdm2 by multiple pathways leading to p53 stabilization , 2006, Oncogene.

[124]  T. Jacks,et al.  STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications , 2001, Oncogene.

[125]  I Berger,et al.  In vitro generated antibodies specific for telomeric guanine-quadruplex DNA react with Stylonychia lemnae macronuclei , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[126]  L. Penn,et al.  Reflecting on 25 years with MYC , 2008, Nature Reviews Cancer.

[127]  D. Bearss,et al.  Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[128]  E. De Pauw,et al.  Electrospray mass spectrometry of telomeric RNA (TERRA) reveals the formation of stable multimeric G-quadruplex structures. , 2010, Journal of the American Chemical Society.

[129]  D. Patel,et al.  Solution structure of the human telomeric repeat d[AG3(T2AG3)3] G-tetraplex. , 1993, Structure.

[130]  B. Guyen,et al.  Synthesis and evaluation of analogues of 10H-indolo[3,2-b]quinoline as G-quadruplex stabilising ligands and potential inhibitors of the enzyme telomerase. , 2004, Organic & biomolecular chemistry.

[131]  M. Eilers,et al.  Contributions of Myc to tumorigenesis. , 2002, Biochimica et biophysica acta.

[132]  L. Hurley,et al.  The importance of negative superhelicity in inducing the formation of G-quadruplex and i-motif structures in the c-Myc promoter: implications for drug targeting and control of gene expression. , 2009, Journal of medicinal chemistry.

[133]  A. Patel,et al.  myc function and regulation. , 1992, Annual review of biochemistry.

[134]  I. Wierstra,et al.  The c-myc promoter: still MysterY and challenge. , 2008, Advances in cancer research.

[135]  Julian Leon Huppert,et al.  G-quadruplexes: the beginning and end of UTRs , 2008, Nucleic acids research.

[136]  S. Balasubramanian,et al.  Small molecule-mediated inhibition of translation by targeting a native RNA G-quadruplex. , 2010, Organic & biomolecular chemistry.

[137]  S. Berberich,et al.  PuF/NM23-H2/NDPK-B transactivates a human c-myc promoter-CAT gene via a functional nuclease hypersensitive element. , 1995, Oncogene.

[138]  Roger A. Jones,et al.  A dimeric DNA interface stabilized by stacked A.(G.G.G.G).A hexads and coordinated monovalent cations. , 2000, Journal of molecular biology.

[139]  C. Woodcock,et al.  Electron microscopy of DNA conformations in spinach chloroplasts. , 1968, Journal of molecular biology.