Metastases suppressor NM23-H2 interaction with G-quadruplex DNA within c-MYC promoter nuclease hypersensitive element induces c-MYC expression

Regulatory influence of the G-quadruplex or G4 motif present within the nuclease hypersensitive element (NHE) in the promoter of c-MYC has been noted. On the other hand, association of NM23-H2 to the NHE leads to c-MYC activation. Therefore, NM23-H2 interaction with the G4 motif within the c-MYC NHE presents an interesting mechanistic possibility. Herein, using luciferase reporter assay and chromatin immunoprecipitation we show NM23-H2 mediated c-MYC activation involves NM23-H2-G4 motif binding within the c-MYC NHE. G4 motif complex formation with recombinant NM23-H2 was independently confirmed using fluorescence energy transfer, which also indicated that the G4 motif was resolved to an unfolded state within the protein-bound complex. Taken together, this supports transcriptional role of NM23-H2 via a G4 motif.

[1]  M. Fry,et al.  Formation and properties of hairpin and tetraplex structures of guanine-rich regulatory sequences of muscle-specific genes , 2005, Nucleic acids research.

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

[3]  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.

[4]  John W. Rooney,et al.  Human NM23/Nucleoside Diphosphate Kinase Regulates Gene Expression through DNA Binding to Nuclease-Hypersensitive Transcriptional Elements , 2000, Journal of bioenergetics and biomembranes.

[5]  Alexander Rich,et al.  Z-DNA: the long road to biological function , 2003, Nature Reviews Genetics.

[6]  M. Zajac-Kaye,et al.  Myc oncogene: a key component in cell cycle regulation and its implication for lung cancer. , 2001, Lung cancer.

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

[8]  M. Kawahara,et al.  Association of nucleoside diphosphate kinase nm23-H2 with human telomeres. , 1998, Biochemical and biophysical research communications.

[9]  P. Steeg,et al.  Nm23/Nucleoside Diphosphate Kinase in Human Cancers , 2000, Journal of bioenergetics and biomembranes.

[10]  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.

[11]  Y. Singh,et al.  Nucleoside diphosphate kinase from Mycobacterium tuberculosis cleaves single strand DNA within the human c-myc promoter in an enzyme-catalyzed reaction , 2005, Nucleic acids research.

[12]  G K Lewis,et al.  Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product , 1985, Molecular and cellular biology.

[13]  K. Anderson,et al.  Telomerase inhibition and cell growth arrest by G-quadruplex interactive agent in multiple myeloma. , 2003, Molecular cancer therapeutics.

[14]  R. Moyzis,et al.  Structure-function correlations of the insulin-linked polymorphic region. , 1996, Journal of molecular biology.

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

[16]  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.

[17]  R. Wells,et al.  Non-B DNA Conformations, Genomic Rearrangements, and Human Disease* , 2004, Journal of Biological Chemistry.

[18]  Haiyong Han,et al.  The cationic porphyrin TMPyP4 down-regulates c-MYC and human telomerase reverse transcriptase expression and inhibits tumor growth in vivo. , 2002, Molecular cancer therapeutics.

[19]  R. Wells,et al.  Unusual DNA structures in the adenovirus genome. , 1986, The Journal of biological chemistry.

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

[21]  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.

[22]  Jan Postberg,et al.  Telomere end-binding proteins control the formation of G-quadruplex DNA structures in vivo , 2005, Nature Structural &Molecular Biology.

[23]  K. Bomsztyk,et al.  Protocol for the fast chromatin immunoprecipitation (ChIP) method , 2006, Nature Protocols.

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

[25]  B. Liu,et al.  NM23-H1 and NM23-H2 Repress Transcriptional Activities of Nuclease-hypersensitive Elements in the Platelet-derived Growth Factor-A Promoter* , 2002, The Journal of Biological Chemistry.

[26]  Alastair I.H. Murchie,et al.  Retinoblastoma susceptibility genes contain 5' sequences with a high propensity to form guanine-tetrad structures , 1992, Nucleic Acids Res..

[27]  T. Chakrabarti,et al.  Amino Acid Residues Involved in Autophosphorylation and Phosphotransfer Activities Are Distinct in Nucleoside Diphosphate Kinase from Mycobacterium tuberculosis* , 2004, Journal of Biological Chemistry.

[28]  G. W. Hatfield,et al.  DNA topology-mediated control of global gene expression in Escherichia coli. , 2002, Annual review of genetics.

[29]  A. Puisieux,et al.  Metastasis: a question of life or death , 2006, Nature Reviews Cancer.

[30]  J. Shklover,et al.  MyoD uses overlapping but distinct elements to bind E-box and tetraplex structures of regulatory sequences of muscle-specific genes , 2007, Nucleic acids research.

[31]  P. Lou,et al.  Verification of antiparallel G-quadruplex structure in human telomeres by using two-photon excitation fluorescence lifetime imaging microscopy of the 3,6-Bis(1-methyl-4-vinylpyridinium)carbazole diiodide molecule. , 2006, Analytical chemistry.

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

[33]  E. Postel.  Multiple Biochemical Activities of NM23/NDP Kinase in Gene Regulation , 2003, Journal of bioenergetics and biomembranes.

[34]  P. Balagurumoorthy,et al.  Structure and stability of human telomeric sequence. , 1994, The Journal of biological chemistry.

[35]  H. Izumiya,et al.  Cloning and Functional Analysis of the ndk1 Gene Encoding Nucleoside-diphosphate Kinase in Schizosaccharomyces pombe(*) , 1995, The Journal of Biological Chemistry.

[36]  Yiqiang Zhao,et al.  Extensive selection for the enrichment of G4 DNA motifs in transcriptional regulatory regions of warm blooded animals , 2007, FEBS letters.

[37]  P. Giguère,et al.  Nm23-H2 Interacts with a G Protein-coupled Receptor to Regulate Its Endocytosis through an Rac1-dependent Mechanism* , 2004, Journal of Biological Chemistry.

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

[39]  J. Beneken,et al.  Mutational analysis of NM23-H2/NDP kinase identifies the structural domains critical to recognition of a c-myc regulatory element. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[40]  K. Usdin,et al.  The Chicken -Globin Gene Promoter Forms a Novel Cinched Tetrahelical Structure (*) , 1996, The Journal of Biological Chemistry.

[41]  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.

[42]  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.

[43]  Andreas Krause,et al.  A standard curve based method for relative real time PCR data processing , 2005, BMC Bioinformatics.

[44]  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.

[45]  E. Raymond,et al.  Effects of cationic porphyrins as G-quadruplex interactive agents in human tumor cells. , 1999, Cancer research.

[46]  B. Hoffman,et al.  The proto-oncogene c-myc and apoptosis , 1998, Oncogene.

[47]  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.

[48]  Stephen Neidle,et al.  A G-quadruplex telomere targeting agent produces p16-associated senescence and chromosomal fusions in human prostate cancer cells. , 2004, Molecular cancer therapeutics.

[49]  J. Backer,et al.  Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells. , 2006, Molecular cell.

[50]  N. Maizels,et al.  Intracellular transcription of G-rich DNAs induces formation of G-loops, novel structures containing G4 DNA. , 2004, Genes & development.

[51]  Dinshaw J. Patel,et al.  Human telomere, oncogenic promoter and 5′-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics , 2007, Nucleic acids research.

[52]  Michael Fry,et al.  Tetraplex DNA and its interacting proteins. , 2007, Frontiers in bioscience : a journal and virtual library.

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

[54]  I. Lascu,et al.  The Catalytic Mechanism of Nucleoside Diphosphate Kinases , 2000, Journal of bioenergetics and biomembranes.

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

[56]  Stephen Neidle,et al.  The design of G-quadruplex ligands as telomerase inhibitors. , 2003, Mini reviews in medicinal chemistry.

[57]  C. Horak,et al.  Translational approaches using metastasis suppressor genes , 2006, Journal of bioenergetics and biomembranes.

[58]  J E Talmadge,et al.  Evidence for a novel gene associated with low tumor metastatic potential. , 1988, Journal of the National Cancer Institute.

[59]  M. Inouye,et al.  The gene for nucleoside diphosphate kinase functions as a mutator gene in Escherichia coli. , 1995, Journal of molecular biology.

[60]  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.

[61]  Samer Khateb,et al.  Homodimeric MyoD Preferentially Binds Tetraplex Structures of Regulatory Sequences of Muscle-specific Genes* , 2005, Journal of Biological Chemistry.

[62]  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..

[63]  S. Neidle,et al.  G‐quadruplexes as therapeutic targets , 2000, Biopolymers.

[64]  S. Kyin,et al.  Catalysis of DNA cleavage and nucleoside triphosphate synthesis by NM23-H2/NDP kinase share an active site that implies a DNA repair function. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[65]  T. Amagasa,et al.  Overexpression of nm23-H2/NDP kinase B in a human oral squamous cell carcinoma cell line results in reduced metastasis, differentiated phenotype in the metastatic site, and growth factor-independent proliferative activity in culture. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[66]  P. Pečinka,et al.  DNA tetraplex formation in the control region of c-myc. , 1998, Nucleic acids research.

[67]  M. Lacombe,et al.  A human NDP-kinase B specifically binds single-stranded poly-pyrimidine sequences. , 1995, Nucleic acids research.

[68]  Yingwu Xu,et al.  Structure-based mutational and functional analysis identify human NM23-H2 as a multifunctional enzyme. , 2002, Biochemistry.