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PMID: 10331650 Published · ppublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Involvement of PARP and poly(ADP-ribosyl)ation in the early stages of apoptosis and DNA replication.

Molecular and cellular biochemistry ·Vol. 193 ·No. 1-2 ·1999-03-00 ·Pages 137-48

Simbulan-Rosenthal CM, Rosenthal DS, Iyer S, Boulares H, Smulson ME

Abstract

We have focused on the roles of PARP and poly(ADP-ribosyl)ation early in apoptosis, as well as during the early stages of differentiation-linked DNA replication. In both nuclear processes, a transient burst of PAR synthesis and PARP expression occurs early, prior to internucleosomal DNA cleavage before commitment to apoptosis as well as at the round of DNA replication prior to the onset of terminal differentiation. In intact human osteosarcoma cells undergoing spontaneous apoptosis, both PARP and PAR decreased after this early peak, concomitant with the inactivation and cleavage of PARP by caspase-3 and the onset of substantial DNA and nuclear fragmentation. Whereas 3T3-L1, osteosarcoma cells, and immortalized PARP +/+ fibroblasts exhibited this early burst of PAR synthesis during Fas-mediated apoptosis, neither PARP-depleted 3T3-L1 PARP-antisense cells nor PARP -/- fibroblasts showed this response. Consequently, whereas control cells progressed into apoptosis, as indicated by induction of caspase-3-like PARP-cleavage activity, PARP-antisense cells and PARP -/- fibroblasts did not, indicating a requirement for PARP and poly(ADP-ribosyl)ation of nuclear proteins at an early reversible stage of apoptosis. In parallel experiments, a transient increase in PARP expression and activity were also noted in 3T3-L1 preadipocytes 24 h after induction of differentiation, a stage at which approximately 95% of the cells were in S-phase, but not in PARP-depleted antisense cells, which were consequently unable to complete the round of DNA replication required for differentiation. PARP, a component of the multiprotein DNA replication complex (MRC) that catalyzes viral DNA replication in vitro, poly(ADP-ribosyl)ates 15 of approximately 40 MRC proteins, including DNA pol alpha, DNA topo I, and PCNA. Depletion of endogenous PARP by antisense RNA expression in 3T3-L1 cells results in MRCs devoid of any DNA pol alpha and DNA pol delta activities. Surprisingly, there was no new expression of PCNA and DNA pol alpha, as well as the transcription factor E2F-1 in PARP-antisense cells during entry into S-phase, suggesting that PARP may play a role in the expression of these proteins, perhaps by interacting with a site in the promoters for these genes.

MeSH Terms
3T3 Cells Animals Apoptosis Caspase 3 Caspases/metabolism DNA Replication/physiology HL-60 Cells Humans Jurkat Cells Mice Osteosarcoma/metabolism Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases/metabolism,physiology Proteins/metabolism,physiology RNA, Antisense/metabolism S Phase Time Factors Tumor Cells, Cultured
Chemicals
Proteins RNA, Antisense Parp1 protein, mouse Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases CASP3 protein, human Casp3 protein, mouse Caspase 3 Caspases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Simbulan-Rosenthal C M
Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, DC 20007, USA.
Rosenthal D S
Iyer S
Boulares H
Smulson M E
References (67)
67 references, click to expand
  1. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme.
    Cell. 1993 Nov 19;75(4):641-52 PMID: 8242740
  2. Possible involvement of poly(ADP-ribosyl) polymerase in triggering stress-induced apoptosis.
    Exp Cell Res. 1994 Jun;212(2):367-73 PMID: 8187831
  3. Proliferation is required for induction of terminal differentiation of Friend erythroleukemia cells.
    Biochem Cell Biol. 1992 Jul;70(7):555-64 PMID: 1449723
  4. Influence of poly(ADP-ribose) polymerase on the enzymatic synthesis of SV40 DNA.
    J Biol Chem. 1991 Feb 15;266(5):3087-100 PMID: 1671570
  5. Effects of 6-aminonicotinamide on cell growth, poly(ADP-ribose) synthesis and nucleotide metabolism.
    Biochem Pharmacol. 1985 Nov 15;34(22):3999-4003 PMID: 2933043
  6. Human DNA polymerase alpha gene: sequences controlling expression in cycling and serum-stimulated cells.
    Mol Cell Biol. 1991 Apr;11(4):2081-95 PMID: 2005899
  7. Fas-mediated apoptosis is modulated by intracellular glutathione in human T cells.
    Eur J Immunol. 1996 May;26(5):1164-9 PMID: 8647182
  8. CPP32/apopain is a key interleukin 1 beta converting enzyme-like protease involved in Fas-mediated apoptosis.
    J Biol Chem. 1996 Jan 26;271(4):1841-4 PMID: 8567626
  9. TFIIF, a basal eukaryotic transcription factor, is a substrate for poly(ADP-ribosyl)ation.
    Biochem J. 1997 May 15;324 ( Pt 1):249-53 PMID: 9164864
  10. Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease.
    Genes Dev. 1995 Mar 1;9(5):509-20 PMID: 7698643
  11. Inhibition of DNA polymerase alpha, DNA polymerase beta, terminal deoxynucleotidyl transferase, and DNA ligase II by poly(ADP-ribosyl)ation reaction in vitro.
    Biochem Biophys Res Commun. 1985 Apr 16;128(1):61-7 PMID: 3921027
  12. Inhibitors of poly(adenosine diphosphate-ribose) synthesis: effect on other metabolic processes.
    Science. 1984 Feb 10;223(4636):589-91 PMID: 6420886
  13. Qualitative and quantitative differences in the cellular responses mediated through Fas antigen and tumor necrosis factor receptor.
    J Interferon Cytokine Res. 1996 Mar;16(3):259-67 PMID: 8697149
  14. Regulation of the expression or recruitment of components of the DNA synthesome by poly(ADP-ribose) polymerase.
    Biochemistry. 1998 Jun 30;37(26):9363-70 PMID: 9649317
  15. Poly(ADP-ribose) polymerase enhances activator-dependent transcription in vitro.
    Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2261-5 PMID: 9122182
  16. Selective apoptosis of CD4+CD8+ thymocytes by the anti-Fas antibody.
    J Exp Med. 1995 Feb 1;181(2):485-91 PMID: 7530758
  17. Transcription factor E2F is required for efficient expression of the hamster dihydrofolate reductase gene in vitro and in vivo.
    Mol Cell Biol. 1989 Nov;9(11):4994-5002 PMID: 2601705
  18. Poly(ADP-ribosylation) of DNA topoisomerase I from calf thymus.
    J Biol Chem. 1984 Jan 10;259(1):547-54 PMID: 6323415
  19. NAD(+)-dependent repair of damaged DNA by human cell extracts.
    J Biol Chem. 1993 Mar 15;268(8):5480-7 PMID: 7680646
  20. Distinct roles for E2F proteins in cell growth control and apoptosis.
    Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7245-50 PMID: 9207076
  21. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis.
    Nature. 1995 Jul 6;376(6535):37-43 PMID: 7596430
  22. Molecular ordering of the cell death pathway. Bcl-2 and Bcl-xL function upstream of the CED-3-like apoptotic proteases.
    J Biol Chem. 1996 Mar 1;271(9):4573-6 PMID: 8617712
  23. Transient poly(ADP-ribosyl)ation of nuclear proteins and role of poly(ADP-ribose) polymerase in the early stages of apoptosis.
    J Biol Chem. 1998 May 29;273(22):13703-12 PMID: 9593711
  24. Resistance to Fas-mediated apoptosis in human hepatoma cells.
    Oncogene. 1995 Sep 21;11(6):1157-64 PMID: 7566976
  25. Requirement for the expression of poly(ADP-ribose) polymerase during the early stages of differentiation of 3T3-L1 preadipocytes, as studied by antisense RNA induction.
    J Biol Chem. 1995 Jan 6;270(1):119-27 PMID: 7814362
  26. Transcription of the E2F-1 gene is rendered cell cycle dependent by E2F DNA-binding sites within its promoter.
    Mol Cell Biol. 1995 Aug;15(8):4660 PMID: 7623859
  27. Poly(ADP-ribosyl)ation of histone H1 correlates with internucleosomal DNA fragmentation during apoptosis.
    J Biol Chem. 1996 Apr 12;271(15):9129-34 PMID: 8621564
  28. Poly(ADP-ribose)-mediated post-translational modification of chromatin-associated human topoisomerase I. Inhibitory effects on catalytic activity.
    J Biol Chem. 1989 Nov 5;264(31):18687-92 PMID: 2553719
  29. Pivotal role of a DEVD-sensitive step in etoposide-induced and Fas-mediated apoptotic pathways.
    EMBO J. 1996 Oct 15;15(20):5504-12 PMID: 8896444
  30. The cytotoxic cell protease granzyme B initiates apoptosis in a cell-free system by proteolytic processing and activation of the ICE/CED-3 family protease, CPP32, via a novel two-step mechanism.
    EMBO J. 1996 May 15;15(10):2407-16 PMID: 8665848
  31. Interrelationship between poly (ADP-Rib) synthesis, intracellular NAD levels, and muscle or cartilage differentiation from mesodermal cells of embryonic chick limb.
    Proc Natl Acad Sci U S A. 1975 May;72(5):1852-7 PMID: 168579
  32. A human temperature-sensitive p53 mutant p53Val-138: modulation of the cell cycle, viability and expression of p53-responsive genes.
    Oncogene. 1995 Jul 6;11(1):1-6 PMID: 7624116
  33. p53-dependent induction of apoptosis by proteasome inhibitors.
    J Biol Chem. 1997 May 16;272(20):12893-6 PMID: 9148891
  34. E1A-dependent trans-activation of the human MYC promoter is mediated by the E2F factor.
    Proc Natl Acad Sci U S A. 1989 May;86(10):3594-8 PMID: 2524830
  35. A binding site for transcription factor E2F is a target for trans activation of murine thymidine kinase by polyomavirus large T antigen and plays an important role in growth regulation of the gene.
    J Virol. 1993 Apr;67(4):1765-71 PMID: 8445710
  36. Transient formation of DNA strand breaks during the induced differentiation of a human promyelocytic leukaemic cell line, HL-60.
    Nucleic Acids Res. 1987 Apr 24;15(8):3493-502 PMID: 3106933
  37. Human ICE/CED-3 protease nomenclature.
    Cell. 1996 Oct 18;87(2):171 PMID: 8861900
  38. Cleavage of CPP32 by granzyme B represents a critical role for granzyme B in the induction of target cell DNA fragmentation.
    J Biol Chem. 1996 Sep 6;271(36):21709-12 PMID: 8702964
  39. Poly(ADP-ribose) binds to specific domains of p53 and alters its DNA binding functions.
    J Biol Chem. 1998 May 8;273(19):11839-43 PMID: 9565608
  40. Intact cell evidence for the early synthesis, and subsequent late apopain-mediated suppression, of poly(ADP-ribose) during apoptosis.
    Exp Cell Res. 1997 May 1;232(2):313-21 PMID: 9168807
  41. Activation of the CPP32 apoptotic protease by distinct signaling pathways with differential sensitivity to Bcl-xL.
    J Biol Chem. 1996 Jul 26;271(30):17601-4 PMID: 8663611
  42. DNA replication and poly(ADP-ribosyl)ation of chromatin.
    Cytobios. 1989;58(236):19-28 PMID: 2512056
  43. Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis.
    Cancer Res. 1993 Sep 1;53(17):3976-85 PMID: 8358726
  44. Replication factors required for SV40 DNA replication in vitro. I. DNA structure-specific recognition of a primer-template junction by eukaryotic DNA polymerases and their accessory proteins.
    J Biol Chem. 1991 Jan 25;266(3):1950-60 PMID: 1671045
  45. Induction of HL-60 cells to undergo apoptosis is determined by high levels of wild-type p53 protein whereas differentiation of the cells is mediated by lower p53 levels.
    Cell Growth Differ. 1996 Jan;7(1):21-30 PMID: 8788030
  46. Detection of DNA breaks in apoptotic cells utilizing the DNA binding domain of poly(ADP-ribose) polymerase with fluorescence microscopy.
    Nucleic Acids Res. 1997 Apr 1;25(7):1437-41 PMID: 9060441
  47. Differential assay and biological significance of poly(ADP-ribose) polymerase activity in isolated liver nuclei.
    Mutat Res. 1990 Nov;245(3):157-63 PMID: 2122245
  48. Engineered human skin model using poly(ADP-ribose) polymerase antisense expression shows a reduced response to DNA damage.
    J Invest Dermatol. 1995 Jul;105(1):38-43 PMID: 7615974
  49. Expression of the poly(ADP-ribose) polymerase gene following natural and induced DNA strand breakage and effect of hyperexpression on DNA repair.
    Carcinogenesis. 1990 Jan;11(1):123-8 PMID: 2104780
  50. Inhibition of calf thymus type II DNA topoisomerase by poly(ADP-ribosylation).
    EMBO J. 1985 Aug;4(8):2129-34 PMID: 2998783
  51. The role of poly(ADP-ribose) synthesis in toxicity and repair of DNA damage.
    Pharmacol Ther. 1985;31(3):269-93 PMID: 3939630
  52. Role of poly(ADP-ribose) formation in DNA repair.
    Nature. 1992 Mar 26;356(6367):356-8 PMID: 1549180
  53. Overproduction of the poly(ADP-ribose) polymerase DNA-binding domain blocks alkylation-induced DNA repair synthesis in mammalian cells.
    EMBO J. 1993 May;12(5):2109-17 PMID: 8491199
  54. The expression of poly(ADP-ribose) polymerase during differentiation-linked DNA replication reveals that it is a component of the multiprotein DNA replication complex.
    Biochemistry. 1996 Sep 10;35(36):11622-33 PMID: 8794742
  55. Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis.
    Nature. 1996 Apr 25;380(6576):723-6 PMID: 8614469
  56. Degradation of lamin B1 precedes oligonucleosomal DNA fragmentation in apoptotic thymocytes and isolated thymocyte nuclei.
    J Immunol. 1995 Apr 15;154(8):3788-95 PMID: 7535814
  57. Depletion of nuclear poly(ADP-ribose) polymerase by antisense RNA expression: influences on genomic stability, chromatin organization, and carcinogen cytotoxicity.
    Cancer Res. 1994 Sep 1;54(17 ):4627-34 PMID: 8062255
  58. Identification of multiprotein complexes containing DNA replication factors by native immunoblotting of HeLa cell protein preparations with T-antigen-dependent SV40 DNA replication activity.
    J Cell Biochem. 1996 Dec 1;63(3):259-67 PMID: 8913877
  59. Involvement of NAD-poly(ADP-ribose) metabolism in p53 regulation and its consequences.
    Cancer Res. 1995 Sep 1;55(17):3697-701 PMID: 7641178
  60. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase.
    Cell. 1995 Jun 2;81(5):801-9 PMID: 7774019
  61. Activation of the template activity of isolated rat liver nuclei for DNA synthesis and its inhibition by NAD.
    Biochem Biophys Res Commun. 1973 Jul 17;53(2):572-9 PMID: 4352070
  62. Depletion of poly(ADP-ribose) polymerase by antisense RNA expression results in a delay in DNA strand break rejoining.
    J Biol Chem. 1992 Jun 25;267(18):12804-12 PMID: 1618781
  63. Nicotinamide inhibits adipocyte differentiation of 3T3-L1 cells.
    FEBS Lett. 1982 Sep 6;146(1):37-41 PMID: 6216118
  64. Apoptosis and its modulation in human promyelocytic HL-60 cells treated with DNA topoisomerase I and II inhibitors.
    Exp Cell Res. 1993 Aug;207 (2):388-97 PMID: 7688316
  65. Deletion mutants of poly(ADP-ribose) polymerase support a model of cyclic association and dissociation of enzyme from DNA ends during DNA repair.
    Biochemistry. 1994 May 24;33(20):6186-91 PMID: 8193132
  66. Calcium-activated DNA fragmentation in rat liver nuclei.
    J Biol Chem. 1989 Apr 15;264(11):6398-403 PMID: 2703497
  67. Poly(ADP-ribose) polymerase stimulates DNA polymerase alpha by physical association.
    J Biol Chem. 1993 Jan 5;268(1):93-9 PMID: 8416979
Article Info
Journal
Molecular and cellular biochemistry
Abbr.
Mol Cell Biochem
ISSN
0300-8177
Published
1999-03-00
Pages
137-48
Language
English
Region
Netherlands
NLM ID
0364456
Subset
IM
Grants
NCI NIH HHS · CA25344 · United States
NCI NIH HHS · P0I CA74175 · United States
External Links
PubMed source View journal details
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