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Cellular catabolism in apoptosis: DNA degradation and endonuclease activation

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Abstract

Recent research has focused on identifying the biochemical events associated with the apoptotic process. These include specific degradation of the chromatin which was described by Wyllie in 1980 [1], with the report of the appearance of discretely sized DNA fragments from apoptotic rat thymocytes. The fragments corresponded in size to strands of DNA that were cleaved at internucleosomal regions and create a ‘ladder patterns’ when electrophoresed on an agarose gel. Because of its near universality, internucleosomal DNA degradation is considered a diagnostic hallmark of cells undergoing apoptosis. It is of great interest to identify the enzymes involved, and some of the candidates will be discussed.

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Literatur

  1. Wyllie A. (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous nuclease activation. Nature284: 555–556

    Article  PubMed  Google Scholar 

  2. Arends M. and Wyllie A. (1991) Apoptosis: mechanisms and roles in pathology. Int. Rev. Expl. Path32: 223–251

    Google Scholar 

  3. Kerr J., Wyllie A. and Currie A. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer26: 239–257

    PubMed  Google Scholar 

  4. Wyllie A., Kerr J. and Currie A. (1980) Cell death: the significance of apoptosis. Int. Rev. Cytol.68: 251–306.

    PubMed  Google Scholar 

  5. Cohen J. and Duke R. (1984) Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death. J. Immunol.132: 38–42

    PubMed  Google Scholar 

  6. Wyllie A., Morris R., Smith A. and Dunlop D. (1984) Chromatin cleavage in apoptosis: association with condensed chromatin morphology and dependence on macromolecular synthesis. J. Path.142: 67–77

    Article  PubMed  Google Scholar 

  7. Arends M., Morris R. and Wyllie A. (1990) Apoptosis: the role of the endonuclease. Am. J. Path.136: 593–608

    PubMed  Google Scholar 

  8. Compton M. and Cidlowski J. (1992) Thymocyte apoptosis: a model of programmed cell death. Trends Endocr. Metab.3: 17–23

    Article  Google Scholar 

  9. Schwartzman R. and Cidlowski J. (1993) Mechanism of tissue-specific induction of internucleosomal deoxyribonucleic acid cleavage activity and apoptosis by glucocorticoids. Endocrinology133: 591–599

    Article  PubMed  Google Scholar 

  10. Oberhammer F., Fritsch G., Pavelka M., Froschl G., Tiefenbacher R., Purchio T. and Schulte-Hermann R. (1992) Induction of apoptosis in cultured hepatocytes and in the regressing liver by transforming growth factor-bl occurs without activation of an endonuclease. Toxic. Lett.64/65: 701–704

    Article  Google Scholar 

  11. Ucker D., Obermiller P., Eckhart W., Apgar J., Berger N. and Meyers J. (1992). Genome digestion is a dispensible consequence of physiological cell death mediated by cytotoxic T lymphocytes. Mol. Cell. Biol.12: 3060–3069

    PubMed  Google Scholar 

  12. Filipski J., Leblanc J., Youdale T., Sikorska M. and Walker P. (1990) Periodicity of DNA folding in higher order chromatin structures. EMBO J.9: 1319–1327

    PubMed  Google Scholar 

  13. Compton M. and Cidlowski J. (1986) Rapid in vivo effects of glucocorticoids on the intergrity of rat lymphocyte genomic DNA. Endocrinology118: 39–45

    Google Scholar 

  14. Duke R., Chernenak R. and Cohen J. (1983) Endogenous endonuclease-induced DNA fragmentation: an early event in cell-mediated cytolysis. Proc. Natl Acad. Sci. USA80: 6361–6365

    PubMed  Google Scholar 

  15. Hallick R., Chelm B., Gray, P. and Orozco E. (1977) Use of aurintricarboxylic acid as an inhibitor of nucleases during nucleic acid isolation. Nuc. Acids Res.4: 3055–3064

    Google Scholar 

  16. Dowd D., MacDonald P., Komm B., Haussler M. and Miesfeld R. (1992) Stable expression of the calbindin-D28K complementary DNA interferes with the apoptotic pathway in lymphocytes. Mol. Endocrinol.6: 1843–1848

    Article  PubMed  Google Scholar 

  17. Clawson G., Norbeck L., Hatem C., Rhodes C., Amiri P., McKerrow J., Patierno S. and Fiskum G. (1992) Ca2+-regulated serine protease associated with the nuclear scaffold. Cell Growth Diff.3: 827–838

    PubMed  Google Scholar 

  18. Smyth M. Browne K., Thia K., Apostolidis V., Kershaw M. and Trapani J. (1994) Hypothesis: cytotoxic lymphocyte granule serine proteases active target cell endonucleases to trigger apoptosis. Clin. Expl. Pharmacol. Physiol.21: 67–70

    Google Scholar 

  19. Brown D., Sun X.-M. and Cohen G. (1993) Dexamethasone-induced apoptosis involves cleavage of DNA to large fragments prior to internucleosomal fragmentation. J. Biol. Chem.268: 3027–3039

    Google Scholar 

  20. Bortner C. and Cidlowski J. (1996) The role of volume regulation in apoptosis. Am. J. Physiology (in press)

  21. Peitsch M., Polzar B., Stephan H., Crompton I. and MacDonald H. (1993). Characterization of the endogenous deoxyribonuclease involved in nuclear DNA degradation during apoptosis (programmed cell death). EMBO J.12: 371–377

    PubMed  Google Scholar 

  22. Barry M. and Eastman A. (1993) Identification of deoxyribonuclease II as an endonuclease involved in apoptosis. Archs Biochem. Biophys.300: 440–450

    Article  Google Scholar 

  23. Tanuma S.-I. and Shiokawa D. (1994) Multiple forms of nuclear deoxyribonuclease in rat thymocytes. Biochem. Biophys. Res. Commun.203: 789–797

    Article  PubMed  Google Scholar 

  24. Gaido M. and Cidlowski J. (1991) Identification, purification and characterization of a calcium-dependent endonuclease (NUC18) from apoptotic rat thymocytes. J. Biol. Chem.266: 18580–18585

    PubMed  Google Scholar 

  25. McConkey D., Hatzell P., Nicotera P. and Orrenius S. (1989) Calcium-activated DNA fragmentation kills immature thymocytes. FASEB J.3: 1843–1849

    PubMed  Google Scholar 

  26. Ribeiro J. and Carson D. (1993) Ca2+/Mg2+-dependent endonuclease from human spleen: purification, properties, and role in apoptosis. Biochemistry32: 9129–9136

    Article  PubMed  Google Scholar 

  27. Zhivotovsky B., Nicotera P., Bellomo G., Hanson K. and Orrenius S. (1993) Ca2+ and endonuclease activation in radiation-induced lymphoid cell death. Expl Cell Res.207: 163–170

    Article  Google Scholar 

  28. Miyauchi K., Ogawa M., Shibata T., Matsuda K., Mori T., Ito, K., Minamiura N. and Yamamoto T. (1986) Development of a radioimmunoassay for human deoxyribonuclease I. Clin. Chim. Acta154: 115–123

    Article  PubMed  Google Scholar 

  29. Eastman A. (1994) Deoxyribonuclease II in apoptosis and the significance of intracellular acidification. Cell growth Diff.1: 7–11

    Google Scholar 

  30. Compton M. and Cidlowski J. (1987) Identification of a glucocorticoid-induced nuclease in thymocytes. J. Biol. Chem.262: 8288–8292

    PubMed  Google Scholar 

  31. Rosenthal A. and Lacks S. (1977) Nuclease detection in SDS-polyacrylamide gel electrophoresis. Analyt. Biochem.80: 76–90

    Article  PubMed  Google Scholar 

  32. Cleveland D., Fischer S., Kirschner M. and Laemmli U. (1977) Peptide mapping by limited proteolysid in sodium dodecyl sulfate and analysis by gel elecrophoresis. J. Biol. Chem.252: 1102–1106

    PubMed  Google Scholar 

  33. Caron-Leslie L. and Cidlowski J. (1991) Similar actions of glucocorticoids and calcium on the regulation of apoptosis in S49 cells. Mol. Endocrinol.5: 1169–1179

    PubMed  Google Scholar 

  34. Caron-Leslie L. and Cidlowski J. (1994) Apoptosis: signal transduction and modes of activation. In: Ovarian Cell Interactions: Genes to Physiology, pp. 1–22. New York, Springer-Verlag

    Google Scholar 

  35. Montague J., Gaido M., Frye C. and Cidlowski J. (1994) A calcium-dependent nuclease from apoptotic rat thymocytes is homologous with cyclophilin. J. Biol. Chem.269: 18877–18880

    PubMed  Google Scholar 

  36. Handschumacher R., Harding M., Rice J. and Drugge R. (1984) Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science226: 544–546

    PubMed  Google Scholar 

  37. Koletsky A., Harding M. and Handschumacher R. (1986) Cyclophilin: distribution and variant properties in normal and noeplastic tissues. J. Immunol.137: 1054–1059

    PubMed  Google Scholar 

  38. Ryffel B., Woerly G., Greiner B., Haendler B., Mihatsch M. and Foxwell B. (1991) Distribution of the cyclosporine binding protein cyclophilin in human tissues. Immunology72: 399–404

    PubMed  Google Scholar 

  39. Dawson T., Steiner J., Lyons W., Fotuhi M., Blue M. and Snyder S. (1994) The immunophilins, FK506 binding protein and cyclophilin, are discretely localized in the brain: relationship to calcineurin. Neuroscience62: 569–580

    Article  PubMed  Google Scholar 

  40. Tropschug M., Nicholson D., Hartl F., Kohler H., Pfanner N., Wachter E. and Neupert W. (1988) Cyclosporin A-binding protein (cyclophilin) onNeurospora crassa: one gene codes for both the cytosolic and mitochondrial forms. J. Biol. Chem.263: 14433–14444

    PubMed  Google Scholar 

  41. McDonald M., Ardito T., Marks W., Kashgarian M. and Lorber M. (1992) The effect of cyclosporine administration on the cellular distribution and content of cyclophilin. Transplantation53: 460–466

    PubMed  Google Scholar 

  42. Zydowsky L., Ho S., Baker C., McIntyre K. and Walsh C. (1992) Overexpression, purification, and characterization of yeast cyclophilins A and B. Protein Science1: 961–969

    PubMed  Google Scholar 

  43. Price E., Zydowsky L., Jin M., Baker C., McKeon F. and Walsh C. (1991) Human cyclophilin B: a second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence. Proc. Natl Acad. Sci. USA88: 1903–1907

    PubMed  Google Scholar 

  44. Liu J. and Walsh C. (1990) Peptidyl-prolyl cis-trans-isomerase fromEscherichia coli: a periplasmic homolog of cyclophilin that is not inhibited by cyclosporin A. Proc. Natl Acad. Sci. USA87: 4028–4032

    PubMed  Google Scholar 

  45. Hayano T., Takahashi N., Kato S., Maki N. and Suzuki M. (1991) Two distinct forms of peptidylprolyl-cis-trans-isomearse are expressed separately in periplasmic and cytoplasmic compartments ofEscherichia coli cells. Biochemistry30: 3041–3048

    Article  PubMed  Google Scholar 

  46. Kok R., Christoffels V., Vosman B. and Hellingwerf K. (1994) A gene ofAcinetobacter calcoacticus BD413 encodes a periplasmic peptidyl-prolylcis-trans isomerase of the cyclophilin sub-class that is not essential for growth. Biochim. biophys. Acta1219: 601–606

    PubMed  Google Scholar 

  47. Caroni P., Rothenfluh A., McGlynn E. and Schneider C. (1991) S-cyclophilin: new member of the cyclophilin family associated with the secretory pathway. J. Biol. Chem.266: 10739–10742

    PubMed  Google Scholar 

  48. Tanida I., Yanagida M., Maki N., Yagi S., Namiyama F., Kobayashi T., Hayano T., Takahashi N. and Suzuki M. (1991) Yeast cyclophilin-related gene encodes a nonessential second peptidyl-prolylcis-trans isomerase associated with the secretory pathway. Transplant Proc.23: 2856–2861

    PubMed  Google Scholar 

  49. Takahashi N., Hayano T. and Suzuki M. (1989) Peptidyl-prolylcis-trans isomerase is the cyclosporin A-binding protein cyclophilin. Nature337: 473–475

    Article  PubMed  Google Scholar 

  50. Sigal N., Dumont F., Durette P., Siekierka J., Peterson L., Rich D., Dunlap B., Staruch M., Melino M., Koprak S., Williams B. and Pisano J. (1991) Is cyclophilin involved in the immunosuppressive and nephrotoxic mechanism of action of cyclosporin A? J. Expl Med.173: 619–628

    Article  Google Scholar 

  51. Haendler B., Keller P., Hiestand P., Kocher H., Wegmann G. and Movva N. (1989) Yeast cyclophilin: isolation and characterization of the protein, cDNA and gene. Gene83: 39–46

    Article  PubMed  Google Scholar 

  52. Liu J., Farmer J., Lane W., Friedman J., Weissman I. and Schreiber S. (1991) Calcineurin is a common target of cyclophilin-cyclosporin A FKBP-FK506 complexes. Cell66: 1–9

    Article  PubMed  Google Scholar 

  53. Tropschug M., Barthelmess I. and Neupert W. (1989) Sensitivity to cyclosporin A is mediated by cyclophilin inNeurospora crassa andSaccharomyces serevisiae. Nature342: 953–955

    Article  PubMed  Google Scholar 

  54. Krummrei U., Bang R., Schmidtchen R. Brune K. and Band H. (1995) Cyclophilin-A is a zinc-dependent DNA binding protein in macrophages. FEBS Lett371: 47–51

    Article  PubMed  Google Scholar 

  55. Chatellard-Gruaz D., Saurat J.-H. and Siegenthaler G. (1994) Differential expression of cyclophilin isoforms during keratinocyte differentiation. Biochem. J.303: 863–867

    PubMed  Google Scholar 

  56. Ratajczak T., Carrello A., Mark P., Warner B., Simpson R., Moritz R. and House A. (1993) The cyclophilin component of the unactivated estrogen receptor contains a tetratricopeptide repeat domain and shares identity with p59 FKBP59). J. Biol. Chem.268: 13187–13192

    PubMed  Google Scholar 

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Montague, J.W., Cidlowski, J.A. Cellular catabolism in apoptosis: DNA degradation and endonuclease activation. Experientia 52, 957–962 (1996). https://doi.org/10.1007/BF01920104

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