Poly(ADP-Ribosyl)ation of Chromosomal Proteins, Epigenetic Regulation and Human Genomic Integrity in Health and Disease

  • Rafael Alvarez-Gonzalez
Part of the Protein Reviews book series (PRON, volume 13)


The reproducible and accurate expression of genetic information and the integrity of the human genome, both temporally and topographically, rely heavily on the biochemical ability of nuclear proteins to physically interact with each other, as well as with DNA and RNA, at the molecular level. The strength and specificity of these interactions is primarily determined by the intracellular concentrations of each molecule present. Whereas, the affinity is dictated by the collective primary, secondary, tertiary and quaternary structures of the polypeptides themselves, notwithstanding the intrinsic physicochemical and structural properties of the different types of nucleic acids involved. For the most part, the interactions of DNA with protein molecules occur spontaneously in chromatin because the appropriately folded structures of nuclear proteins are adopted prior to their nucleoplasmic internalization via active and passive transport mechanisms. Once transported into the cell nucleus, most proteins whether, structural in nature, like the histones localized within highly compacted interphase chromatin, or as functional enzymes that modulate chromatin dynamics, such as DNA and RNA polymerases (the catalysts responsible for DNA replication, DNA repair, and transcription) are frequently regulated by unique epigenetic mechanisms of amino acid specific covalent chemical modification, e.g., phosphorylation, acetylation, SUMOylation, nitrosylation, and poly(ADP-ribosyl)ation, just to list a few. Interestingly, while most of these biochemical pathways may be ubiquitous to the cytosolic and plasma membrane compartments, the modification of chromatin proteins via ADP-ribose polymerization, especially when catalyzed by poly(ADP-ribose) polymerases 1 and 2 (PARP-1 and PARP-2), exclusively localizes within the nucleoplasm. Emphasis is placed here to review the current state of the latter, particularly as it pertains to the balance between human health and disease.


PARP Inhibitor Genomic Integrity Vide Infra Chromatin Protein Epigenetic Pathway 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Althaus, F.R. (1992). Poly ADP-ribosylation: a histone shuttle mechanism in DNA excision repair. J. Cell Sci. 102:663–670.PubMedGoogle Scholar
  2. Alvarez-Gonzalez, R., Juarez-Salinas, H., Jacobson, E.L., et al. (1983). Evaluation of immobilized boronates for studies of adenine and pyridine nucleotide metabolism. Anal. Biochem. 135:69–77.PubMedCrossRefGoogle Scholar
  3. Alvarez-Gonzalez, R., and Jacobson, M.K. (1987). Characterization of polymers of adenosine diphosphate ribose generated in Vitro and in Vivo. Biochemistry 26:3218–3224.PubMedCrossRefGoogle Scholar
  4. Alvarez-Gonzalez, R. (1988). 3′-deoxyNAD as a substrate for poly(ADP-ribose) polymerase and the reaction mechanism of poly(ADP-ribose) elongation. J. Biol. Chem. 263: 17690–17696.PubMedGoogle Scholar
  5. Alvarez-Gonzalez, R. (ed) (1999). ADP-ribosylation reactions: from bacterial pathogenesis to cancer. Kluwer, Dordrecht/Boston/London.Google Scholar
  6. Alvarez-Gonzalez, R., Spring, H., Muller, M., et al. (1999). Selective loss of poly(ADP-ribose) and the 85 kDa fragment of poly(ADP-ribose) polymerase in nucleoli during alkylation-induced apoptosis in HeLa cells. J. Biol. Chem. 274:32122–32126.PubMedCrossRefGoogle Scholar
  7. Alvarez-Gonzalez, R. (2001). PARP-regulation of eukaryotic gene expression. Survival or Death? Trends Genet. 17:607–608.CrossRefGoogle Scholar
  8. Alvarez-Gonzalez, R. (2007). Genomic maintenance: the p53 poly(ADP-ribosyl)ation connection. Sci. STKE (415):pe68.CrossRefGoogle Scholar
  9. Atorino, L., Alvarez-Gonzalez, R., Cardone, A., et al. (2000). Metabolic changes in the poly(ADP-ribosyl)ation pathway of differentiating rat germinal cells. Arch. Biochem. Biophys. 381:111–118.PubMedCrossRefGoogle Scholar
  10. Bartha, E., Kiss, G.N., Kalman, E., et al. (2008). Effect of L-2286, a poly(ADP-ribose) polymerase inhibitor and enalapril on myocardial remodeling and heart failure. J. Cardiovasc. Pharmacol. 52:253–261.PubMedCrossRefGoogle Scholar
  11. Beneke, S., and Burkle, A. (2007). Poly(ADP-ribosyl)ation in mammalian aging. Nucleic Acids Res. 35:7456–7465.PubMedCrossRefGoogle Scholar
  12. Benjamin, R.C., and Gill, D.M. (1980). ADP-ribosylation in mammalian cell ghosts. Dependence of poly(ADP-ribose) synthesis on strand breakage on DNA. J. Biol. Chem. 255:10493–10501.PubMedGoogle Scholar
  13. Beard, W.A., and Wilson, S.H. (2006). Structure and mechanism of DNA polymerase beta. Chem. Rev. 106:361–382.PubMedCrossRefGoogle Scholar
  14. Booz, G.W. (2007). PARP inhibitors and heart failure. Translational medicine caught in the act. Congestive Heart Fail. 13:105–112.CrossRefGoogle Scholar
  15. Bouchard, V.J., Rouleau, M., Poirier, G.G. (2003). PARP-1, a determinant of cell survival in response to DNA damage. Exp. Hematol. 31:446–454.PubMedCrossRefGoogle Scholar
  16. Bromme, H.J., and Holtz, J. (1996). Apoptosis in the heart: when and why. Mol. Cell. Biochem. 163–164:261–275.PubMedCrossRefGoogle Scholar
  17. Chambon, P., Weill, J.D., Mandel, P. (1963). Nicotinamide mononucleotide activation of a new DNA-dependent polyadenylic acid synthesizing enzyme. Biochem. Biophys. Res. Commun. 11:9–43.CrossRefGoogle Scholar
  18. Chang, W.J., and Alvarez-Gonzalez, R. (2001). The sequence specific DNA-binding of NF-κB is reversibly regulated by the automodification reaction of poly(ADP-ribose) polymerase-1. J. Biol. Chem. 276:47664–47670.PubMedCrossRefGoogle Scholar
  19. Chatteerjee, S., Berger, S.J., Berger, N.A. (1999). Poly(ADP-ribose) polymerase: a guardian of the genome that facilitates DNA repair by protecting against DNA recombination. Mol. Cell. Biochem. 193:23–30.CrossRefGoogle Scholar
  20. Choi, D.W. (1997). At the scene of ischemic brain injury. Is PARP a perp. Nature (Med) 3:1073–1074.CrossRefGoogle Scholar
  21. Conde, C., Mark, M., Oliver, F.J., Huber, A., et al. (2001). Loss of poly(ADP-ribose) polymerase 1 causes increased tumor latency in p53 deficient mice. EMBO J. 20:3535–3543.PubMedCrossRefGoogle Scholar
  22. Csiszar, A., Wang, M., Lakkata, E.G., et al. (2008). Inflammation and endothelial dysfunction during aging: role of NF-kappa B. J. Appl. Physiol. 105:1333–1341.PubMedCrossRefGoogle Scholar
  23. De Boer, R.A., van Veldhuisen, D.J., van der Wijk, J., et al. (2000). Additional use of immunostaining for active caspase 3 and cleaved actin and PARP fragments to detect apoptosis in patients with chronic heart failure. J. Card. Fail. 6:330–337.PubMedCrossRefGoogle Scholar
  24. Donawho, C.K., Luo, Y., Penning, T.D., et al. (2007). ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in pre-clinical tumor models. Clin. Cancer Res. 13:2728–2737.PubMedCrossRefGoogle Scholar
  25. El-Domyati, M.M., Al-Din, A.B., Barakat, M.T., et al. (2008). Deoxyribonucleic acid repair and apoptosis in testicular germ cells of aging fertile men: the role of the poly(adenosine diphosphate ribosyl)ation pathway. Fertil. Steril. 91(Suppl 5):2221–2229PubMedGoogle Scholar
  26. Endres, M., Wang, Z.Q., Namura, S., et al. (1997). Ischemic brain injury is mediated by the activation by poly(ADP-ribose) polymerase. J. Cereb. Blood Flow Metab. 17:1143–1151.PubMedCrossRefGoogle Scholar
  27. Gospodinov, A., and Herceg, Z. (2009). Chromatin. The entry and exit from DNA repair. In: Vidal, C.J. (ed) Post-translational Modifications of Proteins, Springer, New York.Google Scholar
  28. Grube, K., and Burkle, A. (1992). Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span. Proc. Natl. Acad. Sci. U.S.A. 89:11759–11763.PubMedCrossRefGoogle Scholar
  29. Haddad, M., Beray-Berthat, V., Coqueran, B., et al. (2008). Reduction of hemorrhagic transformation by PJ34, a poly(ADP-ribose) polymerase inhibitor after permanent focal cerebral ischemia in mice. Eur. J. Pharmacol. 588:52–57.PubMedCrossRefGoogle Scholar
  30. Hassa, P.O., Buerki, C., Lombardi, C., et al. (2003). Transcriptional co-activation of nuclear factor-κB-dependent gene expression by p300 is regulated by poly(ADP-ribose) polymerase-1. J. Biol. Chem. 278:45145–45153.PubMedCrossRefGoogle Scholar
  31. Izzo, A., Kamieniarz, K., Schneider, R. (2008). The histone H1 family: specific members, specific functions? Biol. Chem. 389:333–343.PubMedCrossRefGoogle Scholar
  32. Jeoung, D., Lim, Y., Lee, E.B., et al. (2004). Identification of autoantibody against poly(ADP-ribose) polymerase (PARP) fragment as a serological marker in systemic lupus erythematosus. J. Autoimmunity 22: 87–94.CrossRefGoogle Scholar
  33. Joashi, U.C., Greenwood, K., Taylor, D.L., et al. (1999). Poly(ADP-ribose) polymerase cleavage precedes neuronal cell death in the hippocampus and cerebellum following injury to the development rat forebrain. Eur. J. Neurosci. 11:91–100. PubMedCrossRefGoogle Scholar
  34. Juarez-Salinas, H., Sims, J.L., Jacobson, M.K. (1979). Poly(ADP-ribose) levels in carcinogen-treated cells. Nature (London) 282:740–741.CrossRefGoogle Scholar
  35. Kawaichi, K., Ueda, K., Hayaishi, O. (1981). Multiple autopoly(ADP-ribosyl)ation of rat liver poly(ADP-ribose) synthetase: Mode of modification and properties of automodified synthetase. J. Biol. Chem. 256:9483–9489.PubMedGoogle Scholar
  36. Kouzarides, T. (2007). Chromatin modifications and their function. Cell 128:693–705.PubMedCrossRefGoogle Scholar
  37. Kumari, S.R., Alvarez-Gonzalez, R., Mendoza-Alvarez, H. (1998). Functional interactions of p53 with poly(ADP-ribose) polymerase (PARP) during apoptosis following DNA-damage: covalent poly(ADP-ribosyl)ation by exogenous PARP and non-covalent binding of p53 to Mr 85,000 proteolytic fragment. Cancer Res. 58:5075–5078.PubMedGoogle Scholar
  38. Lane, D.P. (1992). Cancer. p53- Guardian of the genome. Nature (London) 358:15–16.CrossRefGoogle Scholar
  39. Lindall, A.W., and Lazarow, L. (1964). A critical study of pyridine nucleotide concentrations in normal fed, normal fasted and diabetic rat liver. Metabolism 13:259–271.CrossRefGoogle Scholar
  40. Loetscher, P., Alvarez-Gonzalez, R., Althaus, F.R. (1987). Poly(ADP-ribose) may signal changing metabolic conditions to the chromatin of mammalian cells. Proc. Natl. Acad. Sci. U.S.A. 84: 1286–1289.PubMedCrossRefGoogle Scholar
  41. Malecka, K.A., Ho, W.C., Marmorstein, R. (2009). Crystal structure of a p53 core tetramer bound to DNA. Oncogene 28:325–333.PubMedCrossRefGoogle Scholar
  42. Masutani, M., Suzuki, H., Kamada, N., et al. (1999). Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptosotocyn-induced diabetes. Proc. Natl. Acad. Sci. U.S.A. 96:2301–2304.PubMedCrossRefGoogle Scholar
  43. Mendoza-Alvarez, H., and Alvarez-Gonzalez, R. (1993). Poly(ADP-ribose) polymerase is a catalytic dimer and the automodification reaction is intermolecular. J. Biol. Chem. 268:22575–22580.PubMedGoogle Scholar
  44. Mendoza-Alvarez, H., and Alvarez-Gonzalez, R. (2001). Regulation of p53 sequence-specific binding by covalent poly(ADP-ribosyl)ation. J. Biol. Chem. 276:36425–36430.PubMedCrossRefGoogle Scholar
  45. Mendoza-Alvarez, H., and Alvarez-Gonzalez, R. (1999). Biochemical characterization of mono(ADP-ribosyl)ated poly(ADP-ribose) polymerase. Biochemistry 38:3948–3953.PubMedCrossRefGoogle Scholar
  46. Messmer, U.K., Winkel, G., Briner, G.A., et al. (2000). Suppression of apoptosis by glucocorticoids in glomerulal endothelial cells: effects on proapoptotic pathways. Br. J. Pharmacol. 29:1673–1683.CrossRefGoogle Scholar
  47. Molnar. A., Toth, A., Bagi, Z., et al. (2006). Activation of the poly(ADP-ribose) polymerase pathway in human heart failure. Mol. Med. 12:143–152.PubMedCrossRefGoogle Scholar
  48. Moroni, F., and Chiarugi, A. (2009). Post-ischemic brain damage: targeting PARP-1 within the ischemic neurovascular units as a realistic avenue to stroke treatment. FEBS J. 276:36–45.PubMedCrossRefGoogle Scholar
  49. Negri, C., Scovassi, A.I., Cerino, A., et al. (1990). Autoantibodies to poly(ADP-ribose) polymerase in autoimmune diseases. Autoimmunity 6:203–209.PubMedCrossRefGoogle Scholar
  50. Oliver, F.J., Menissier-de Murcia, J., Nacci, C., et al. (1999). Resistance to endotoxic shock as a consequence to defective NF-κB activation in poly(ADP-ribose) polymerase-1 deficient mice. EMBO J. 18:4446–4454.PubMedCrossRefGoogle Scholar
  51. Okamoto, H. (1999). The CD38-cyclic ADP-ribose signaling system in insulin secretion. Mol. Cell. Biochem. 193:115–118.PubMedCrossRefGoogle Scholar
  52. Pacheco-Rodriguez, G., and Alvarez-Gonzalez, R. (1999). Measurement of poly(ADP-ribose) glycohydrolase activity by high resolution polyacrylamide gel electrophoresis: specific inhibition by histones and nuclear matrix proteins. Mol. Cell. Biochem. 193:13–18.PubMedCrossRefGoogle Scholar
  53. Pacher, P., and Szabo, C. (2008). Role of peroxynitrate-poly(ADP-ribose) polymerase pathway in human disease. Am. J. Pathol. 173:1–13.CrossRefGoogle Scholar
  54. Perkin, N.D., and Gilmore, T.D. (2006). Good cop, bad cop: the different faces of NF-kappa B. Cell Death Differ. 13:759–772.CrossRefGoogle Scholar
  55. Pietsch, E.C., Sykes, S.M., MacMahon, S.B., et al. (2008). The p53 family and programmed cell death. Oncogene 27:6507–6521.PubMedCrossRefGoogle Scholar
  56. Pillai, J.B., Isbatan, A., Imai, S.I., et al. (2005). Poly(ADP-ribose) polymerase 1-dependent cardiac myocyte cell death during heart failure is mediated by NAD + cell depletion and reduced Sir2α deacetylase activity. J. Biol. Chem. 280:43121–43130.PubMedCrossRefGoogle Scholar
  57. Plummer, R., Jones, C., Middleton, M., et al. (2008). Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG-14699, in combination with temozolomide in patients with advanced solid tumors. Clin. Cancer. Res. 14:7917–7923.PubMedCrossRefGoogle Scholar
  58. Rosen, A., and Casciola-Rosen, L. (2004). Altered autoantigen structure in Sjogren’s syndrome: implications for the pathogenesis of autoimmune tissue damage. Crit. Rev. Oral Biol. Med. 15:156–164.PubMedCrossRefGoogle Scholar
  59. Scovassi, A.I., and Poirier, G.G. (1999). Poly(ADP-ribosyl)ation and apoptosis. Mol. Cell. Biochem. 199:125–137.PubMedCrossRefGoogle Scholar
  60. Simbulan-Rosenthal, C.M., Rosenthal, D.S., Luo, R. B., et al. (2001). Poly(ADP-ribosyl)ation of p53 in vitro and in vivo modulates binding to its DNA consensus sequence. Neoplasia 3:179–188.PubMedCrossRefGoogle Scholar
  61. Suganuma, T., and Workman, J.L. (2008). Crosstalk among histone modifications. Cell 135:604–607.PubMedCrossRefGoogle Scholar
  62. Tong, W.M., Cortes, U., Wang, Z.Q. (2001). Poly(ADP-ribose) polymerase: a guardian angel protecting the genome and suppressing tumorigenesis. Biochim. Biophys. Acta 1552:27–37.PubMedGoogle Scholar
  63. Tremethik, D.J. (2007). Higher-ordered structures of chromatin: the elusive 30 nm fiber. Cell 128:651–654.CrossRefGoogle Scholar
  64. Tye, B.K., and Swayer, S. (2000). The hexameric eukaryotic MCM helicase: building symmetry from non-identical parts. J. Biol. Chem. 275:34833–34836.PubMedCrossRefGoogle Scholar
  65. Valdor, R., Schreiber, V., Saenz, J., et al. (2008). Regulation of NFAT by poly(ADP-ribose) polymerase in T cells. Mol. Immunol. 24:1863–1871.CrossRefGoogle Scholar
  66. Wieler, S., Cagne, J.P., Vaziri, H., et al. (2003). Poly(ADP-ribose) polymerase-1 is a positive regulator of the p53-mediated G1 cycle arrest response following ionizing radiation. J. Biol. Chem. 278:18914–18921.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Graduate School of Biomedical Sciences, Institute for Cancer ResearchUniversity of North Texas Health Science Center at Fort WorthFort WorthUSA

Personalised recommendations