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. 2007 May 1;8(4):455–464. doi: 10.1111/j.1582-4934.2004.tb00470.x

Glutathione depletion‐induced chromosomal DNA fragmentation associated with apoptosis and necrosis

Yoshihiro Higuchi 1,✉
PMCID: PMC6740256  PMID: 15601574

Abstract

Chromosomal DNA and mitochondrial dysfunctions play a role on mammalian cell death induced by oxidative stress. The major biochemical dysfunction of chromosome is the presence of an ordered cleavage of the DNA backborn, which is separated and visualized as an electrophoretic pattern of fragments. Oxidative stress provides chromatin giant DNA, 200‐800 kb or 50‐300 kb high molecular weight (HMW) DNA and internucleosomal DNA fragments are produced during apoptosis or necrosis induced by oxidative stress such as gluthione (GSH) depletion in several types of mammalian cells. Reactive oxygen species (ROS)‐mediated DNA fragmentation is Mitochondrial dysfunction on decrease of trans membrane potential, accumulation of ROS, membrane permeability transition transition and release of apoptotic factors during apoptosis or necrosis has been implicated. This review refers to the correlation of chromo‐somal DNA fragmentation and apoptosis or necrosis induced by GSH depletion, and the possible mechanisms of oxidative stress‐induced cell death.

Keywords: apoptosis, giant DNA fragmentation, GSH depletion, lipid peroxidation, mitochondria dysfunction, necrosis, oxidative stress

References

  • 1. Wyllie A.H., Kerr J.F.R., Currie A.R., Cell death: the significance of apoptosis, Int Rev Cytol. 68: 251–306, 1990. [DOI] [PubMed] [Google Scholar]
  • 2. Higuchi Y., Matsukawa S., Appearance of 1‐2 Mb giant DNA fragments as an early common response leading to cell death induced by various substances which cause oxidative stress, Free Radic Biol Med., 23: 90–99, 1997. [DOI] [PubMed] [Google Scholar]
  • 3. Carson D.A., Ribeiro J.M. Apoptosis and disease, Lancet, 341: 1251–1254, 1993. [DOI] [PubMed] [Google Scholar]
  • 4. Schwartz L.M., Smith S.W., Jone M.E.E., Osbone B.A., Do all programmed cell deaths occur via apoptosis Proc Natl Acad Sci.USA 90: 980–984, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Schwartz D.C., Cantor C.R., Separation of yeast chromosome‐size DNAs by pulsed field gradient gel electrophoresis, Cell, 37: 67–75, 1984. [DOI] [PubMed] [Google Scholar]
  • 6. Higuchi Y., Measurement of DNA double‐strand breaks with giant DNA and high molecular weight DNA fragments by pulsed‐field gel electrophoresis, Methods Mol Biol 186: 161–170, 2002. [DOI] [PubMed] [Google Scholar]
  • 7. Higuchi Y., Matsukawa S., Active oxygen‐mediated chromosomal 1–2 Mbp giant DNA fragmentation into internucleosomal DNA fragmentation in apoptosis of glioma cells induced by glutamate, Free Radic Biol Med, 24: 418–426, 1998. [DOI] [PubMed] [Google Scholar]
  • 8. Higuchi Y., Glutathione depletion induces giant DNA fragmentation associated with apoptosis or necrosis In: Nesaretnam K, Packer L, eds. Micronutrients and Health: Molecular Biological Mechanisms. Champaign :AOCS Press, 202–216, 2001. [Google Scholar]
  • 9. Matsukawa S., Higuchi Y., The nature of giant DNA molecules produced from nuclear chromosome DNA by active oxygen producing agents In: Devies KJA, ed. Oxidative damage and repair. New York :Pergamon, 197–201, 1991. [Google Scholar]
  • 10. Cohen G.M., Sun X., Fearnhead H., MacFarlane M., Brown D.G., Snowden R.T., Dinsdale D., Formation of large molecular weight fragments of DNA is a key committed step of apoptosis in thymocytes, J Immunology, 153: 507–516, 1994. [PubMed] [Google Scholar]
  • 11. Higuchi Y., Matsukawa S., Glutathione depletion induces giant DNA and high molecular weight DNA fragmentation associated with apoptosis through lipid peroxidation and protein kinase C activation in C6 glioma cells, Arch Biochem Biophys, 363: 33–42, 1999. [DOI] [PubMed] [Google Scholar]
  • 12. Wyllie A.H., Glucocorticoid‐induced apoptosis is associated with endogeneous endonuclease activation, Nature, 284: 555–556, 1980. [DOI] [PubMed] [Google Scholar]
  • 13. Peitsch M.C., Muller C., Tschopp J., DNA fragmentation during apoptosis is caused by frequent single‐strandcuts, Nucleic Acids Res, 21: 4206–4209, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Oberhammer F., Wilson J.W., Dive C., Morris I.D., Hickman J.A., Wakeling E., Walker P.R., Sikorska M., Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation, EMBO J, 12: 3679–3684, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Susin S.A., Lorenzo H.K., Zamzami N., Marzo I., Snow B.E., Brothers G.M., Mangion J., Jacotot E., Costantini P., Loeffler M., Larochette N., Goodlett D.R., Aebersold R., Siderovski D.P., Penhinger J.M., Kroemer G., Molecular characterization of mitochondrial apoptosis‐inducing factor, Nature 397: 441–446, 1999. [DOI] [PubMed] [Google Scholar]
  • 16. Bortner C.D., Oldenburg N.E., Cidlowski J.A., The role of DNA fragmentation in apoptosis. Trends Cell Biol, 5: 21–26, 1995. [DOI] [PubMed] [Google Scholar]
  • 17. Lagarkova M.A., Iarovaia O.V., Razin S.V., Large‐scale fragmentation of mammalian DNA in the course of apoptosis proceeds via excision of chromosomal DNA loops and their oligomers, J Biol Chem, 270: 20239–20241, 1995. [DOI] [PubMed] [Google Scholar]
  • 18. Zhivotovsky B, Orrenius S. Involvement of Ca2+ in the formation of high molecular weight DNA fragments in thymocyte apoptosis. Biochem Biophys Res Commun. [DOI] [PubMed]
  • 19. Higuchi Y., Chromosomal DNA fragmentation in apoptosis and necrosis induced by oxidative stress, Biochem Pharmacol, 66: 1527–1535, 2003. [DOI] [PubMed] [Google Scholar]
  • 20. Jacobson M.D., Reactive oxygen species and programmed cell death, Trends Biochem Sci, 21: 83–86, 1996. [PubMed] [Google Scholar]
  • 21. Li Y., Maher P., Schubert D., Requirement for cGMP in nerve cell death caused by glutathione depletion. J. Cell Biol., 139: 1317–1324, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Rattan, R.R , Murphy, T. M. , Baraban J.M., Macromolecular synthesis inhibitors prevent oxidative stress‐induced apoptosis in embryonic cortical neurons by shunting cysteine from protein synthesis to glutathione, J. Neurosci, 14: 4385–4312, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Hayashi T., Sakurai M., Itoyama Y., Abe K., Oxidative damage and breakage of DNA in rat brain after transient MCA occlusion, Brain Res, 832: 159–163, 1999. [DOI] [PubMed] [Google Scholar]
  • 24. Maher P., Davis J.M., The role of monoamine metabolism in oxidative glutamate toxicity, J Neuroscience, 16: 6394–6401, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Cohen G., Farooqui R., Kesler N., Parkinson disease: Anew link between monoamine oxidase and mitochondrial electron flow, Proc Natl Acad Sci. USA, 94: 4890–4894, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Samanta S., Perkinton M.S., Morgan M., Williams R.J., Hydrogen peroxide enhances signal‐responsive arachidonic acid release from neurons: Role of mitogenactivated protein kinase, J Neurochem, 70: 2082–2090, 1998. [DOI] [PubMed] [Google Scholar]
  • 27. Li Y., Maher P., Schubert D., A role for 12‐lipoxygenase in nerve cell death caused by glutathione depletion, Neuron, 19: 453–463, 1997. [DOI] [PubMed] [Google Scholar]
  • 28. Yamamoto S., Mammalian lipoxygenases; molecular structures and functions, Biochim Biophys Acta, 1128: 117–131, 1992. [DOI] [PubMed] [Google Scholar]
  • 29. Higuchi Y., Yoshimoto T., Promoting effect of polyunsaturated fatty acids on chromosomal giant DNA fragmentation associated with cell death induced by glutathion depletion, Free Radic Res., 38: 649–658, 2004. [DOI] [PubMed] [Google Scholar]
  • 30. Tang D., Chen Y. Q., Honn K.V., Arachidonate lipoygenases as essential regulations of cell survival and apoptosis, Proc Natl Acad Sci USA, 93: 5241, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Higuchi Y., Polyunsaturated fatty acids promote 8‐hydroxy‐2‐deoxyguanosine formation through lipid peroxidation under the glutamate‐induced GSH depletion in rat glioma cells, Arch Biochem Biophys, 292: 65–70, 2001. [DOI] [PubMed] [Google Scholar]
  • 32. Higuchi Y., Yoshimoto T., Archidonic acid converts the glutathione depletion‐induced apoptosis to necrosis by promoting lipid peroxidation in glioma cells, Arch Biochem Biophys, 400: 133–140, 2002. [DOI] [PubMed] [Google Scholar]
  • 33. Ochu E.E., Rothwell N.J., Waters C.M., Caspases mediate 6‐hydroxydopamine‐induced apoptosis but not necrosis in PC12 cells, J Neurochem, 70: 2637–2640, 1998. [DOI] [PubMed] [Google Scholar]
  • 34. Enari M., Sakahira H., Yokoyama H., Okawa K., Iwamatsu A. Nagata S., A caspase‐activated DNase that degrades DNA during apoptosis and its inhibitor ICAD, Nature, 391: 43–50, 1998. [DOI] [PubMed] [Google Scholar]
  • 35. Armstrong R.C., Aja T.J., Hoang K.D., Gaur S., Bai X., Alnemri E.S., Litwack G., Karanewsky D.S., Fritz C., Tomaselli K.J., Activation of the CED3/ICE‐related protease CPP32 in cerebellar granule neurons undergoing apoptosis but not necrosis, J Neuroscience, 17: 553–562, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Cummings B.S., Mchowat J., Schnellmann R.G., Phospholipase A2 in cell injyry and death, J Pharmacol Exp Ther, 294: 793–799, 2000. [PubMed] [Google Scholar]
  • 37. Holtsberg F.W., Steiner M.R., Keller J.N., Mark R.J., Mattson M.P., Steiner S.M., Lysophosphatidic acid induces necrosis and apoptosis in hippocampal neurons, J Neurochem, 70: 66–76, 1998. [DOI] [PubMed] [Google Scholar]
  • 38. Tan S., Wood M., Maher P., Oxidative stress induces a form of programmed cell death with characteristics of both apoptosis and necrosis in neuronal cells, J Neurochem, 71: 95–105, 1998. [DOI] [PubMed] [Google Scholar]
  • 39. Green D.R., Reed J.C., Mitochondria and apoptosis, Science, 281: 1309–1312 1998. [DOI] [PubMed] [Google Scholar]
  • 40. Merad‐Boudia M., Nicole A., Santiard‐Baron D., Saille C., Ceballos‐Picot I., Mitochondrial impairment as an early event in the process of apoptosis induced by glutathione depletion in neuronal cells: Relevance to Parkinsons disease, Biochem Pharmacol, 56: 645–655, 1998. [DOI] [PubMed] [Google Scholar]
  • 41. Fawthrop D.J., Boobis A.R., Davies D.S., Mechanisms of cell death, Arch Toxicology, 65: 437–444, 1991. [DOI] [PubMed] [Google Scholar]
  • 42. Herceg Z., Wang Z. Q., Failure of poly (ADP‐ribose) polymerase cleavage by caspases leads to induction of necrosis and enhanced apoptosis. Mol Cell Biol, 19: 5124–5133, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Kass G.E.N., Eriksson J.E., Weis M., Orrenius S., Chow S.C., Chromatin condensation during apoptosis requires ATP, Biochem J, 318: 749–752, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Lelli J.L., Becks L.L., Dabrowska M.I., Hinshaw D.B., ATP converts necrosis to apoptosis in oxidant‐injured endotherial cells, Free Radic Biol Med, 25: 694–702, 1998. [DOI] [PubMed] [Google Scholar]
  • 45. Ankarcrona M., Dypbukt J.M., Bonfoco E., Zhivotovsky B., Orrenius S., Lipton S.A., Nicotera P., Glutamate‐induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function, Neuron, 15: 961–973, 1995. [DOI] [PubMed] [Google Scholar]
  • 46. Yuan J., Lipinski M., Degterev A., Diversity in the mechanisms of neuronal cell death, Neuron, 40: 401–413, 2003. [DOI] [PubMed] [Google Scholar]
  • 47. Liu X., Zou H., Slaughter C., Wang X., DFF, a heterodimeric protein that functions downstream of caspase‐3 to trigger DNA fragmentation during apoptosis, Cell, 89: 175–184, 1997. [DOI] [PubMed] [Google Scholar]
  • 48. Eguchi Y., Srinivasan A., Tomaselli K.J., Shimizu S., and Tsujimoto Y., ATP‐dependent steps in apoptotic signal transduction, Cancer Res, 59: 2174–2181, 1999. [PubMed] [Google Scholar]
  • 49. Lorenzo H.K., Susin S.A., Penninger J., Kroemer G., Apoptosis inducing factor (AIF): a phylogenetically old, caspase‐independent effector of cell death, Cell Death Differ., 6: 516–524, 1999. [DOI] [PubMed] [Google Scholar]

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