Poly(ADP-ribosyl)ation, Genetic Instability, and Aging

  • A. Bürkle
  • K. Grube
  • J.-H. Küpper
Part of the Reihe der Villa Vigoni book series (VILLA VIGONI, volume 1)

Abstract

Poly(ADP-ribosyl)ation is a posttranslational protein modification catalyzed by poly(ADP-ribose) polymerase (PARP), a highly conserved nuclear enzyme which uses nicotinamide-adenine dinucleotide (NAD) as substrate (for review, see [1]). The DNA-binding domain of the enzyme specifically binds to DNA single-or double-strand breaks, resulting in enzyme activation. Thus, treatment of cells with chemical or physical carcinogens induces a dose-dependent stimulation of polymer synthesis and turnover. To understand the biological function(s) of poly(ADP-ribosyl)ation, NAD analogues have been extensively used as competitive inhibitors of poly(ADP-ribosyl)ation in intact cells. Such inhibitors (e.g.,benzamide and derivatives such as 3-aminobenzamide) have no influence on cell growth (at concentrations of 1 mM or lower) nor are they mutagenic or carcinogenic. They potentiate, however, cytotoxicity and chromosomal damage induced by carcinogen treatment, e.g., alkylating agents or ionizing radiation. These and other findings led to the view that poly(ADP-ribosyl)ation plays a role in DNA repair.

Keywords

Lymphoma Adenosine Oligomer Methotrexate Fluorescein 

Abbreviations

3AB

3-aminobenzamide

AF

amplification factor

DHFR

dihydrofolate reductase

EF

enhancement factor

MNNG

N-methyl-N’-nitro-N-nitrosoguanidine

MTX

methotrexate

PARP

poly(ADP-ribose) polymerase

PE

plating efficiency

SV40

Simian virus 40

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References

  1. 1.
    Althaus FR, Richter C (1987) ADP-ribosylation of proteins. Enzymology and biological significance. (Molecular biology, biochemistry and biophysics 37) Springer, Berlin, Heidelberg, New YorkCrossRefGoogle Scholar
  2. 2.
    Alitalo K, Schwab M (1986) Oncogene amplification in tumor cells. Adv Cancer Res 47: 235–281PubMedCrossRefGoogle Scholar
  3. 3.
    Schimke RT (1988) Gene amplification in cultured cells. J Biol Chem 263: 5989–5992PubMedGoogle Scholar
  4. 4.
    Bürkle A (1989) Altern und genetische Instabilität. Futura 2: 19–22 (Zeitschrift des Boehringer Ingelheim Fonds)Google Scholar
  5. 5.
    Bürkle A, Meyer T, Hilz H, zur Hausen H (1987) Enhancement of N-methyl-N’-nitro-N-nitrosoguanidine-induced DNA amplification in a simian virus 40-transformed Chinese hamster cell line by 3-aminobenzamide. Cancer Res (1987) 47: 3632–3636PubMedGoogle Scholar
  6. 6.
    Bürkle A, zur Hausen H (1987) Influence of poly(ADP-ribose) metabolism on carcino-gen-inducible DNA amplification. In: zur Hausen H, Schlehofer JR (eds) The role of DNA amplification in carcinogenesis. Lippincott, Philadelphia, pp 126–132Google Scholar
  7. 7.
    Bürkle A, Heilbronn R, zur Hausen H (1990) Potentiation of carcinogen-induced methotrexate resistance and dihydrofolate reductase gene amplification by inhibitors of poly(adenosine diphosphate-ribose) polymerase. Cancer Res 50: 5756–5760PubMedGoogle Scholar
  8. 8.
    Bürkle A (1989) Inhibition of carcinogen-inducible DNA amplification in a simian virus 40-transformed hamster cell line by ethacridine or ethanol. Cancer Res 49: 2584–2587PubMedGoogle Scholar
  9. 9.
    Shmookler-Reis RJ, Goldstein S (1980) Loss of reiterated DNA sequences during serial passage of human diploid fibroblasts. Cell 21: 739–749PubMedCrossRefGoogle Scholar
  10. 10.
    Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during aging of human fibroblasts. Nature 345: 458–460PubMedCrossRefGoogle Scholar
  11. 11.
    Lundblad V, Szostak JL (1989) A mutant with a defect in telomere elongation leads to senescence in yeast. Cell 57: 633–643PubMedCrossRefGoogle Scholar
  12. 12.
    Kunisada T, Yamagishi H, Ogita Z-I, Kirakawa T, Mitsui Y (1985) Appearance of extrachromosomal circular DNAs during in vivo and in vitro aging of mammalian cells. Mech Aging Dev 29:89–99PubMedCrossRefGoogle Scholar
  13. 13.
    Hart RW, Setlow RB (1974) Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species. Proc Natl Acad Sci USA 71:2169–2173PubMedCrossRefGoogle Scholar
  14. 14.
    Hart RW, Sacher GA, Hoskins TL (1979) DNA repair in a short-and a long-lived rodent species. J Gerontol 34: 808–817PubMedGoogle Scholar
  15. 15.
    Francis AA, Lee WH, Regan JD (1981) The relationship of DNA excision repair of ultraviolet induced lesions to the maximum life span of mammals. Mech Aging Dev 16: 181–189PubMedCrossRefGoogle Scholar
  16. 16.
    Pero RW, Holmgren K, Persson L (1985) Gamma-radiation induced ADP-ribosyl transferase activity and mammalian longevity. Mutat Res 142: 69–73PubMedCrossRefGoogle Scholar
  17. 17.
    Berger NA, Petzold SI (1985) Identification of minimal size requirements of DNA for activation of poly(ADP-ribose) polymerase. Biochemistry 24: 4352–4355PubMedCrossRefGoogle Scholar
  18. 18.
    Grube K, Küpper JH, Bürkle A (1991) Direct stimulation of poly(ADP-ribose) polymerase in permeabilized cells by double-stranded DNA oligomers. Anal Biochem 193: 236–239PubMedCrossRefGoogle Scholar
  19. 19.
    Küpper JH, de Murcia G, Bürkle A (1990) Inhibition of poly(ADP-ribosyl)ation by overexpressing the poly(ADP-ribose) polymerase DNA-binding domain in mammalian cells. J Biol Chem 265: 18721–18724PubMedGoogle Scholar
  20. 20.
    Küpper JH (1990) Thesis, University of Heidelberg, FRGGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1992

Authors and Affiliations

  • A. Bürkle
  • K. Grube
  • J.-H. Küpper

There are no affiliations available

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