dinucleoside phosphates


Summary: A group of compounds which consist of a nucleotide molecule to which an additional nucleoside is attached through the phosphate molecule(s). The nucleotide can contain any number of phosphates.

Top Publications

  1. Burns C, Campagnoli R, Shaw J, Vincent A, Jorba J, Kew O. Genetic inactivation of poliovirus infectivity by increasing the frequencies of CpG and UpA dinucleotides within and across synonymous capsid region codons. J Virol. 2009;83:9957-69 pubmed publisher
  2. Mediero A, Peral A, Pintor J. Dual roles of diadenosine polyphosphates in corneal epithelial cell migration. Invest Ophthalmol Vis Sci. 2006;47:4500-6 pubmed
    ..Based on the pharmacological profile of all the compounds tested, the two main P2Y receptors that exist in these corneal cells are a P2Y(2) receptor accelerating the rate of healing and a P2Y6 receptor that delays this process. ..
  3. Greenbaum B, Levine A, Bhanot G, Rabadan R. Patterns of evolution and host gene mimicry in influenza and other RNA viruses. PLoS Pathog. 2008;4:e1000079 pubmed publisher
    ..As a possible explanation, we suggest that the strong selection pressures acting on these RNA viruses are most likely related to the innate immune response and to nucleotide motifs in the host DNA and RNAs. ..
  4. Peng M, Cui Y, Bi Y, Rothstein S. AtMBD9: a protein with a methyl-CpG-binding domain regulates flowering time and shoot branching in Arabidopsis. Plant J. 2006;46:282-96 pubmed
    ..This pathway is not related to FLC expression as over-expression of FLC in atmbd9-2 restored its flowering time to one similar to that of the wild type, but did not alter the shoot branching phenotype. ..
  5. Baker M, Holloway D, Swaminathan G, Acharya K. Crystal structures of eosinophil-derived neurotoxin (EDN) in complex with the inhibitors 5'-ATP, Ap3A, Ap4A, and Ap5A. Biochemistry. 2006;45:416-26 pubmed
    ..We examine the structure-affinity relationships of these inhibitors and discuss the implications for the design of improved inhibitors. ..
  6. Corrigan R, Abbott J, Burhenne H, Kaever V, GRUNDLING A. c-di-AMP is a new second messenger in Staphylococcus aureus with a role in controlling cell size and envelope stress. PLoS Pathog. 2011;7:e1002217 pubmed publisher
    ..Taken together, these data suggest a function for this novel secondary messenger in controlling cell size of S. aureus and in helping bacteria to cope with extreme membrane and cell wall stress. ..
  7. Ebensen T, Libanova R, Schulze K, Yevsa T, Morr M, Guzman C. Bis-(3',5')-cyclic dimeric adenosine monophosphate: strong Th1/Th2/Th17 promoting mucosal adjuvant. Vaccine. 2011;29:5210-20 pubmed publisher
    ..These results indicated that c-di-AMP exhibits a high potential as adjuvant for the development of mucosal vaccines, in particular when cellular immunity is needed. ..
  8. Parvatiyar K, Zhang Z, Teles R, Ouyang S, Jiang Y, Iyer S, et al. The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response. Nat Immunol. 2012;13:1155-61 pubmed publisher
    ..Our results suggest a mechanism whereby c-di-GMP and c-di-AMP are detected by DDX41, which forms a complex with STING to signal to TBK1-IRF3 and activate the interferon response. ..
  9. Woodward J, Iavarone A, Portnoy D. c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response. Science. 2010;328:1703-5 pubmed publisher
    ..c-di-AMP thus represents a putative bacterial secondary signaling molecule that triggers a cytosolic pathway of innate immunity and is predicted to be present in a wide variety of bacteria and archea. ..

More Information


  1. Kamegaya T, Kuroda K, Hayakawa Y. Identification of a Streptococcus pyogenes SF370 gene involved in production of c-di-AMP. Nagoya J Med Sci. 2011;73:49-57 pubmed
    ..This in vitro production of c-di-AMP indicated that spyDAC in S. pyogenes actually catalyzes the in vivo biosynthesis of c-di-AMP from ATP. ..
  2. Witte G, Hartung S, Büttner K, Hopfner K. Structural biochemistry of a bacterial checkpoint protein reveals diadenylate cyclase activity regulated by DNA recombination intermediates. Mol Cell. 2008;30:167-78 pubmed publisher
    ..Identification of the diadenylate cyclase domain in other eubacterial and archaeal proteins implies a more general role for c-di-AMP in prokaryotes. ..
  3. Krakowiak A, Pecherzewska R, Kaczmarek R, Tomaszewska A, Nawrot B, Stec W. Evaluation of influence of Ap4A analogues on Fhit-positive HEK293T cells; cytotoxicity and ability to induce apoptosis. Bioorg Med Chem. 2011;19:5053-60 pubmed publisher
  4. Romling U. Great times for small molecules: c-di-AMP, a second messenger candidate in Bacteria and Archaea. Sci Signal. 2008;1:pe39 pubmed publisher
    ..To elucidate the biological importance and molecular mechanisms of action for c-di-AMP and the recently recognized second messenger c-di-GMP will require a multidisciplinary approach. ..
  5. Garrison P, Robinson A, Pekarsky Y, Croce C, Barnes L. Phosphorylation of the human Fhit tumor suppressor on tyrosine 114 in Escherichia coli and unexpected steady state kinetics of the phosphorylated forms. Biochemistry. 2005;44:6286-92 pubmed
  6. Fisher D, McLennan A. Correlation of intracellular diadenosine triphosphate (Ap3A) with apoptosis in Fhit-positive HEK293 cells. Cancer Lett. 2008;259:186-91 pubmed
    ..510pmol/10(6)cells with etoposide. These results support the view that Ap3A is the in vivo Fhit ligand and that an inhibition of Fhit activity is a key element in Fhit-mediated apoptosis. ..
  7. Washenberger C, Han J, Kechris K, Jha B, Silverman R, Barton D. Hepatitis C virus RNA: dinucleotide frequencies and cleavage by RNase L. Virus Res. 2007;130:85-95 pubmed
    ..Thus, RNase L can cleave HCV RNAs efficiently and variably reduced frequencies of UA and UU dinucleotides in HCV RNA ORFs are consistent with the selective pressure of RNase L. ..
  8. Oppenheimer Shaanan Y, Wexselblatt E, Katzhendler J, Yavin E, Ben Yehuda S. c-di-AMP reports DNA integrity during sporulation in Bacillus subtilis. EMBO Rep. 2011;12:594-601 pubmed publisher
    ..Reduced c-di-AMP levels cause a delay in sporulation that can be reversed by external supplementation of the molecule. Thus, c-di-AMP acts as a secondary messenger, coupling DNA integrity with progression of sporulation. ..
  9. Rauch T, Li H, Wu X, Pfeifer G. MIRA-assisted microarray analysis, a new technology for the determination of DNA methylation patterns, identifies frequent methylation of homeodomain-containing genes in lung cancer cells. Cancer Res. 2006;66:7939-47 pubmed
    ..The results support the hypothesis that cancer-associated DNA methylation events do not occur randomly throughout the genome but at least some are targeted by specific mechanisms. ..
  10. Cooper D, Mort M, Stenson P, Ball E, Chuzhanova N. Methylation-mediated deamination of 5-methylcytosine appears to give rise to mutations causing human inherited disease in CpNpG trinucleotides, as well as in CpG dinucleotides. Hum Genomics. 2010;4:406-10 pubmed
    ..We therefore estimate that ?5 per cent of missense/nonsense mutations causing human inherited disease may be attributable to methylation-mediated deamination of 5mC within a CpHpG context. ..
  11. Rao F, See R, Zhang D, Toh D, Ji Q, Liang Z. YybT is a signaling protein that contains a cyclic dinucleotide phosphodiesterase domain and a GGDEF domain with ATPase activity. J Biol Chem. 2010;285:473-82 pubmed publisher
    ..The novel enzymatic activity and stress resistance together point toward a role for YybT in stress signaling and response...
  12. Smith W, Pham T, Lei L, Dou J, Soomro A, Beatson S, et al. Heat resistance and salt hypersensitivity in Lactococcus lactis due to spontaneous mutation of llmg_1816 (gdpP) induced by high-temperature growth. Appl Environ Microbiol. 2012;78:7753-9 pubmed publisher
    ..This study demonstrates that spontaneous mutations can occur during high-temperature growth of L. lactis and that inactivation of llmg_1816 leads to temperature resistance and salt hypersensitivity...
  13. Smith K, Lipchock S, Ames T, Wang J, Breaker R, Strobel S. Structural basis of ligand binding by a c-di-GMP riboswitch. Nat Struct Mol Biol. 2009;16:1218-23 pubmed publisher
  14. Corrigan R, Campeotto I, Jeganathan T, Roelofs K, Lee V, GRUNDLING A. Systematic identification of conserved bacterial c-di-AMP receptor proteins. Proc Natl Acad Sci U S A. 2013;110:9084-9 pubmed publisher
    ..With the identification of these widely distributed c-di-AMP receptor proteins we link the c-di-AMP signaling network to a central metabolic process in bacteria. ..
  15. Mehne F, Gunka K, Eilers H, Herzberg C, Kaever V, Stülke J. Cyclic di-AMP homeostasis in bacillus subtilis: both lack and high level accumulation of the nucleotide are detrimental for cell growth. J Biol Chem. 2013;288:2004-17 pubmed publisher
    ..Taken together, our results support the idea of an important role for c-di-AMP in B. subtilis and suggest that the levels of the nucleotide have to be tightly controlled. ..
  16. Abdul Sater A, Grajkowski A, Erdjument Bromage H, Plumlee C, Levi A, Schreiber M, et al. The overlapping host responses to bacterial cyclic dinucleotides. Microbes Infect. 2012;14:188-97 pubmed publisher
    ..These studies suggest that mammalian macrophages can sense and mount a specific inflammatory response to bacterial dinucleotides. ..
  17. Forsbach A, Nemorin J, Montino C, Muller C, Samulowitz U, Vicari A, et al. Identification of RNA sequence motifs stimulating sequence-specific TLR8-dependent immune responses. J Immunol. 2008;180:3729-38 pubmed
    ..In summary, we describe two classes of single-stranded TLR7/8 and TLR8 RNA agonists with diverse target cell and species specificities and immune response profiles. ..
  18. Bai Y, Yang J, Zhou X, Ding X, Eisele L, Bai G. Mycobacterium tuberculosis Rv3586 (DacA) is a diadenylate cyclase that converts ATP or ADP into c-di-AMP. PLoS ONE. 2012;7:e35206 pubmed publisher
    ..These results provide the molecular basis for designating DacA as a diadenylate cyclase. Our future studies will explore the biological function of this enzyme in M. tuberculosis. ..
  19. Sauer J, Sotelo Troha K, von Moltke J, Monroe K, Rae C, Brubaker S, et al. The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides. Infect Immun. 2011;79:688-94 pubmed publisher
    ..Additionally, Sting is required for the response to c-di-GMP and L. monocytogenes in vivo. Our results provide new functions for Sting in the innate interferon response to pathogens. ..
  20. Mazza C, Segref A, Mattaj I, Cusack S. Co-crystallization of the human nuclear cap-binding complex with a m7GpppG cap analogue using protein engineering. Acta Crystallogr D Biol Crystallogr. 2002;58:2194-7 pubmed
    ..3 A resolution. In both forms, strong extra electron density is observed for the cap analogue and for the N- and C-terminal extensions of CBP20 which was absent or disordered in all previous structures. ..
  21. Fourrier L, Brooks P, Malinge J. Binding discrimination of MutS to a set of lesions and compound lesions (base damage and mismatch) reveals its potential role as a cisplatin-damaged DNA sensing protein. J Biol Chem. 2003;278:21267-75 pubmed
  22. Shah J, Darrah P, Ambrozak D, Turon T, Mendez S, Kirman J, et al. Dendritic cells are responsible for the capacity of CpG oligodeoxynucleotides to act as an adjuvant for protective vaccine immunity against Leishmania major in mice. J Exp Med. 2003;198:281-91 pubmed
    ..Therefore, the combination of LACK antigen and CpG ODN adjuvant leads to the presence of CD11c+ DCs in the draining LN that are capable of vaccinating naive mice in the absence of further antigen or adjuvant. ..
  23. Kumar K, Jenkins J, Jardine A, Shapiro R. Inhibition of mammalian ribonucleases by endogenous adenosine dinucleotides. Biochem Biophys Res Commun. 2003;300:81-6 pubmed
    ..Examination of inhibition under physiological conditions indicates that NADPH, ATP, and Ap(5)A may suppress intracellular RNase activity significantly in vivo. ..
  24. Calero G, Wilson K, Ly T, Rios Steiner J, Clardy J, Cerione R. Structural basis of m7GpppG binding to the nuclear cap-binding protein complex. Nat Struct Biol. 2002;9:912-7 pubmed
  25. Mazza C, Segref A, Mattaj I, Cusack S. Large-scale induced fit recognition of an m(7)GpppG cap analogue by the human nuclear cap-binding complex. EMBO J. 2002;21:5548-57 pubmed
    ..Implications for the transfer of capped mRNAs to eIF4E, required for translation initiation, are discussed. ..
  26. Suspène R, Sommer P, Henry M, Ferris S, Guetard D, Pochet S, et al. APOBEC3G is a single-stranded DNA cytidine deaminase and functions independently of HIV reverse transcriptase. Nucleic Acids Res. 2004;32:2421-9 pubmed
    ..APOBEC3G deamination of dC or dCTP was not detected. In short, APOBEC3G is a single-stranded DNA cytidine deaminase capable of restricting retroviral replication. ..
  27. Millar C, Guy J, Sansom O, Selfridge J, MacDougall E, Hendrich B, et al. Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice. Science. 2002;297:403-5 pubmed
    ..On a cancer-susceptible Apc(Min/+) background, Mbd4-/- mice showed accelerated tumor formation with CpG --> TpG mutations in the Apc gene. Thus MBD4 suppresses CpG mutability and tumorigenesis in vivo. ..
  28. Golebiowski F, Kowara R, Pawelczyk T. Distribution of Fhit protein in rat tissues and its intracellular localization. Mol Cell Biochem. 2001;226:49-55 pubmed
    ..Presented data showing nuclear and plasma membrane localization of Fhit may support the hypothesis concerning Fhit as a signaling molecule. ..
  29. Pintor J, Bautista A, Carracedo G, Peral A. UTP and diadenosine tetraphosphate accelerate wound healing in the rabbit cornea. Ophthalmic Physiol Opt. 2004;24:186-93 pubmed
    ..Mitogen-activated protein kinase (MAPK) cascade inhibitors also abolished the effects of UTP, suggesting that P2Y receptors are coupled to the MAPK cascade, and that this is involved in controlling the rate of epithelial cell migration. ..
  30. Unoki M, Nishidate T, Nakamura Y. ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain. Oncogene. 2004;23:7601-10 pubmed
    ..The data reported here suggest that ICBP90 is involved in cell proliferation by way of methylation-mediated regulation of certain genes. ..
  31. Jardine A, Leonidas D, Jenkins J, Park C, Raines R, Acharya K, et al. Cleavage of 3',5'-pyrophosphate-linked dinucleotides by ribonuclease A and angiogenin. Biochemistry. 2001;40:10262-72 pubmed
  32. Hendrich B, Hardeland U, Ng H, Jiricny J, Bird A. The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites. Nature. 1999;401:301-4 pubmed
    ..The combined specificities of binding and catalysis indicate that this enzyme may function to minimize mutation at methyl-CpG. ..
  33. Sillero M, de Diego A, Osorio H, Sillero A. Dinucleoside polyphosphates stimulate the primer independent synthesis of poly(A) catalyzed by yeast poly(A) polymerase. Eur J Biochem. 2002;269:5323-9 pubmed
    ..These findings together with previous publications from this laboratory point to a potential relationship between dinucleoside polyphosphates and enzymes catalyzing the synthesis and/or modification of DNA or RNA. ..
  34. Kandimalla E, Zhu F, Bhagat L, Yu D, Agrawal S. Toll-like receptor 9: modulation of recognition and cytokine induction by novel synthetic CpG DNAs. Biochem Soc Trans. 2003;31:654-8 pubmed
    ..In the present paper, we review current understanding of structural recognition and functional modulation of TLR9 receptor by second-generation synthetic CpG DNAs and their potential application as wide-spectrum therapeutic agents. ..
  35. Issa J. CpG island methylator phenotype in cancer. Nat Rev Cancer. 2004;4:988-93 pubmed publisher
    ..Furthermore, CIMP-associated cancers seem to have a distinct epidemiology, a distinct histology, distinct precursor lesions and distinct molecular features. ..
  36. Mildvan A, Xia Z, Azurmendi H, Saraswat V, Legler P, Massiah M, et al. Structures and mechanisms of Nudix hydrolases. Arch Biochem Biophys. 2005;433:129-43 pubmed
    ..The overall rate accelerations can be explained by both independent and cooperative effects of these catalytic components. ..
  37. Olesiak M, Stec W, Okruszek A. The synthesis of di- and oligo-nucleotides containing a phosphorodithioate internucleotide linkage with one of the sulfur atoms in a 5'-bridging position. Org Biomol Chem. 2009;7:2162-9 pubmed publisher
    ..It was also found that oligothymidylates containing a single 5'-S-phosphorodithioate linkage form much weaker duplexes with their complementary sequences. ..
  38. Morton B, Dar V, Wright S. Analysis of site frequency spectra from Arabidopsis with context-dependent corrections for ancestral misinference. Plant Physiol. 2009;149:616-24 pubmed publisher
  39. Carmi Levy I, Yannay Cohen N, Kay G, Razin E, Nechushtan H. Diadenosine tetraphosphate hydrolase is part of the transcriptional regulation network in immunologically activated mast cells. Mol Cell Biol. 2008;28:5777-84 pubmed publisher
    ..Thus, we have provided concrete evidence establishing Ap(4)A as a second messenger in the regulation of gene expression. ..
  40. Peng X, Zhang Y, Bai G, Zhou X, Wu H. Cyclic di-AMP mediates biofilm formation. Mol Microbiol. 2016;99:945-59 pubmed publisher
    ..Taken together, our studies reveal a new role of c-di-AMP in mediating biofilm formation through a CabPA/VicR/GtfB signaling network in S. mutans. ..
  41. Heffeter P, Popovic Bijelic A, Saiko P, Dornetshuber R, Jungwirth U, Voevodskaya N, et al. Ribonucleotide reductase as one important target of [Tris(1,10-phenanthroline)lanthanum(III)] trithiocyanate (KP772). Curr Cancer Drug Targets. 2009;9:595-607 pubmed
    ..As also Fe-KP772 as well as free lanthanum exert significant -though less pronounced- cytotoxic/static activities, additional mechanisms are likely to synergise with RR inhibition in the promising anticancer activity of KP772. ..
  42. Zuo H, Chan G, Zhu J, Yeung W, Chan A, Ammer H, et al. Activation state-dependent interaction between G?q subunits and the Fhit tumor suppressor. Cell Commun Signal. 2013;11:59 pubmed publisher
    ..Activated G?q members interact with Fhit through their ?2-?4 region which may result in enhancement of the growth inhibitory effect of Fhit, thus providing a possible avenue for G protein-coupled receptors to modulate tumor suppression. ..
  43. Raza A, Dreis C, Vince R. Photoprotection of DNA (in vitro) by acyclothymidine dinucleosides. Bioorg Med Chem Lett. 2013;23:620-3 pubmed publisher
    ..A biomimetic approach involving structural analogs of nucleic acids can help overcome these limitations. Herein, we show the photoprotective action of acyclothymidine dinucleosides on both plasmid and cellular DNA. ..
  44. Maeda N, Hayashizaki Y. Genome-wide survey of imprinted genes. Cytogenet Genome Res. 2006;113:144-52 pubmed
    ..In this review, we describe genomic imprinting focusing on the history of genome-wide screening. ..
  45. Jankowski V, Karadogan S, Vanholder R, Nofer J, Herget Rosenthal S, van der Giet M, et al. Paracrine stimulation of vascular smooth muscle proliferation by diadenosine polyphosphates released from proximal tubule epithelial cells. Kidney Int. 2007;71:994-1000 pubmed
    ..These epithelial cell metabolic products have vasoregulatory properties while linking the energy supply and tubular function. ..
  46. Schaefer C, Ooi S, Bestor T, Bourc his D. Epigenetic decisions in mammalian germ cells. Science. 2007;316:398-9 pubmed
    ..The restriction of future gene expression by the imposition of heritable methylation patterns in germ cell genomes is characteristic of mammals but is rare in other taxa. ..
  47. Desnous C, Babu B, Moriou C, Mayo J, Favre A, Wengel J, et al. The sugar conformation governs (6-4) photoproduct formation at the dinucleotide level. J Am Chem Soc. 2008;130:30-1 pubmed
    ..Consequently, this study demonstrates that the C2'-endo conformation of the sugar pucker is necessary for (6-4) photoproduct formation. ..
  48. Kim D, Jung J, Lee Y, Kwon H. Novel immunostimulatory phosphodiester oligodeoxynucleotides with CpT sequences instead of CpG motifs. Mol Immunol. 2011;48:1494-504 pubmed publisher
    ..Further investigation of the functional role of PO-CT-ODN may support the future application of PO-CT-ODN in immunotherapeutics. ..
  49. Gu J, Liang G, Xie Y, Schaefer H. Electron attachment to solvated dGpdG: effects of stacking on base-centered and phosphate-centered valence-bound radical anions. Chemistry. 2012;18:5232-8 pubmed publisher
    ..The intrastrand H-bonding patterns revealed in this study also suggest that intrastrand proton transfer might be possible between successive guanines due to electron attachment to DNA single strands. ..
  50. Chou M, Austin C, Kim J. Collective action of hematopoietic cell subsets mediates anti-IL10R1 and CpG tumor immunity. Cancer Immunol Immunother. 2012;61:1055-64 pubmed publisher
  51. Adrien L, Schlecht N, Kawachi N, Smith R, Brandwein Gensler M, Massimi A, et al. Classification of DNA methylation patterns in tumor cell genomes using a CpG island microarray. Cytogenet Genome Res. 2006;114:16-23 pubmed
    ..Such techniques will allow us to identify select groups of CpG island loci that could be used as epigenetic markers for both diagnosis and prognosis in HNSCC. ..
  52. Essex M, Boyce W, Hertzman C, Lam L, Armstrong J, Neumann S, et al. Epigenetic vestiges of early developmental adversity: childhood stress exposure and DNA methylation in adolescence. Child Dev. 2013;84:58-75 pubmed publisher
    ..To the authors' knowledge, this is the first report of prospective associations between adversities in early childhood and the epigenetic conformation of adolescents' genomic DNA. ..
  53. Peine K, Bachelder E, Vangundy Z, Papenfuss T, Brackman D, Gallovic M, et al. Efficient delivery of the toll-like receptor agonists polyinosinic:polycytidylic acid and CpG to macrophages by acetalated dextran microparticles. Mol Pharm. 2013;10:2849-57 pubmed publisher
    ..Overall, we have illustrated a method for enhancing the delivery of these vaccine adjuvants to further enhance the development of Ac-DEX vaccine formulations. ..