Dynamic Interaction between PARP-1, PCNA and p21waf1/cip1

  • Ennio Prosperi
  • A. Ivana Scovassi
Part of the Molecular Biology Intelligence Unit book series (MBIU)


Poly(ADP-ribose) polymerase (PARP-1) plays a crucial role in DNA repair and interacts with many DNA replication/repair factors, including the proliferating cell nuclear antigen (PCNA), a protein involved in many DNA transactions. The association between these proteins in vitro results in the inhibition of PARP-1 activity and of PCNA-dependent DNA synthesis carried out by DNA polymerase δ. In vivo, the interaction of the two proteins has been shown to increase after DNA damage. The activity of PCNA is regulated by p21waf1/cip1, which binds the interdomain connector loop of PCNA in the same region involved in the interaction of PCNA with DNA polymerase δ. This feature enables p21 to compete with DNA polymerase δ to regulate the differential inhibition of DNA replication vs. DNA repair. The finding that PARP- 1 is associated with both PCNA and p21 suggests a possible cooperation of PARP-1 and p21 in regulating the functions of PCNA during DNA replication/repair.


Proliferate Cell Nuclear Antigen Nucleotide Excision Repair Base Excision Repair Werner Syndrome Double Strand Break 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Eki T. Poly (ADP-ribose) polymerase inhibits DNA replication by human replicative DNA polymerase α, β and ε in vitro. FEBS Lett 1994; 356:261–266.PubMedCrossRefGoogle Scholar
  2. 2.
    Simbulan-Rosenthal CM, Rosenthal DS, Boulares H et al. Regulation of the expression or recruitment of components of the DNA synthesome by poly(ADP-ribose) polymerase. Biochemistry 1998; 37:9363–9370.PubMedCrossRefGoogle Scholar
  3. 3.
    Dantzer F, Nasheuer HP, Vonesch JL et al. Functional association of poly(ADP-ribose) polymerase with DNA polymerase α-primase complex: A link between DNA strand break detection and DNA replication. Nucl Acids Res 1998; 26:1891–1898.PubMedCrossRefGoogle Scholar
  4. 4.
    Frouin I, Montecucco A, Biamonti G et al. Cell cycle-dependent dynamic association of cyclin/Cdk complexes with human DNA replication proteins. EMBO J 2002; 21:2485–2495.PubMedCrossRefGoogle Scholar
  5. 5.
    Althaus FR, Richter C. ADP-ribosylation of proteins: Enzymology and biological significance. Springer Verlag, Berlin: 1987.Google Scholar
  6. 6.
    Krupitza G, Cerutti P. ADP-ribosylation of ADPR-transferase and topoisomerase I in intact mouse epidermal cells JB6. Biochemistry 1989; 28:2034–2040.PubMedCrossRefGoogle Scholar
  7. 7.
    Scovassi AI, Mariani C, Negroni M et al. ADP-ribosylation of nonhistone proteins in HeLa cells: Modification of DNA topoisomerase II. Exp Cell Res 1993; 206:177–181.PubMedCrossRefGoogle Scholar
  8. 8.
    Bauer PI, Chen H-J, Kenesi E et al. Molecular interactions between poly(ADP-ribose) polymerase (PARP I) and topoisomerase I (Topo I): Identification of topology of binding. FEBS Lett 2001; 506:239–242.PubMedCrossRefGoogle Scholar
  9. 9.
    Malanga M, Althaus FR. Poly(ADP-ribose) reactivates stalled DNA topoisomerase I and induces DNA strand break resealing. J Biol Chem 2004; 279:5244–5248.PubMedCrossRefGoogle Scholar
  10. 10.
    Canitrot Y, de Murcia G, Salles B. Decreased expression of topoisomerase IIβ in poly(ADP-ribose) polymerase-deficient cells. Nucl Acids Res 1998; 26:5134–5138.PubMedCrossRefGoogle Scholar
  11. 11.
    Pleschke JM, Kleczkowska HE, Strohm M et al. Poly(ADP-ribose) binds to specific domains in DNA damage checkpoint proteins. J Biol Chem 2000; 275:40974–40980.PubMedCrossRefGoogle Scholar
  12. 12.
    Goubin F, Ducommun B. Identification of binding domains on the p21Cip1 cyclin-dependent kinase inhibitor. Oncogene 1995; 10:2281–2287.PubMedGoogle Scholar
  13. 13.
    Gulbis JM, Kelman Z, Hurwitz J et al. Structure of the C-terminal region of p21WAF1/CIP1 complexed with human PCNA. Cell 1996; 87:297–306.PubMedCrossRefGoogle Scholar
  14. 14.
    Gagné J-P, Hunter JM, Labrecque B et al. A proteomic approach to the identification of heterogeneous nuclear ribonucleoproteins as a new family of poly(ADP-ribose)-binding proteins. Biochem J 2003; 371:331–340.PubMedCrossRefGoogle Scholar
  15. 15.
    Durkacz BW, Omidiji O, Gray DA et al. (ADP-ribose)n participates in DNA excision repair. Nature 1980; 283:593–596.PubMedCrossRefGoogle Scholar
  16. 16.
    Jeggo PA. DNA repair: PARP-another guardian angel? Curr Biol 1998; 8:R49–51.PubMedCrossRefGoogle Scholar
  17. 17.
    Bürkle A. Poly(ADP-ribosyl)ation, a DNA damage-driven protein modification and regulator of genomic instability. Cancer Lett 2001; 163:1–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Bouchard VJ, Rouleau M, Poirier GG. PARP-1, a determinant of cell survival in response to DNA damage. Exp Hematol 2003; 31:446–454.PubMedCrossRefGoogle Scholar
  19. 19.
    Shall S, de Murcia G. Poly(ADP-ribose) polymerase-1: What have we learned from the deficient mouse model? Mutat Res 2000; 460:1–15.PubMedGoogle Scholar
  20. 20.
    Dantzer F, Schreiber V, Niedergang C et al. Involvement of poly(ADP-ribose) polymerase in base excision repair. Biochimie 1999; 81:69–75.PubMedCrossRefGoogle Scholar
  21. 21.
    Lavrik OI, Prasad R, Sobol RW et al. Photoaffinity labeling of mouse fibroblast enzymes by a base excision repair intermediate. Evidence for the role of poly(ADP-ribose) polymerase-1 in DNA repair. J Biol Chem 2001; 276:25541–25548.PubMedCrossRefGoogle Scholar
  22. 22.
    Le Page F, Schreiber V, Dhérin C et al. Poly(ADP-ribose) polymerase-1 (PARP-1) is required in murine cell lines for base excision repair of oxidative DNA damage in the absence of DNA polymerase β. J Biol Chem 2003; 278:18471–18477.PubMedCrossRefGoogle Scholar
  23. 23.
    Caldecott KW, Aoufouchi S, Johnson P et al. XRCC1 polypeptide interacts with DNA polymerase β and possibly poly(ADP-ribose) polymerase, and DNA ligase III is a novel molecular “nick sensor” in vitro. Nucl Acids Res 1996; 24:4387–4394.PubMedCrossRefGoogle Scholar
  24. 24.
    Leppard JB, Dong Z, Mackey ZB et al. Physical and functional interaction between DNA ligase IIIα and poly(ADP-ribose) polymerase 1 in DNA single-strand break repair. Mol Cell Biol 2003; 23:5919–5927.PubMedCrossRefGoogle Scholar
  25. 25.
    Mackey ZB, Niedergang C, Ménissier-de Murcia J et al. DNA ligase III is recruited to DNA strand breaks by a zinc finger motif homologous to that of poly(ADP-ribose) polymerase. J Biol Chem 1999; 274:21679–21687.PubMedCrossRefGoogle Scholar
  26. 26.
    Flohr C, Bürkle A, Radicella JP et al. Poly(ADP-ribosyl)ation accelerates DNA repair in a pathway dependent on Cockayne syndrome B protein. Nucl Acids Res 2003; 31:5332–5337.PubMedCrossRefGoogle Scholar
  27. 27.
    Adelfak C, Kontou M, Hirsch-Kauffmann M et al. Physical and functional interaction of the Werner syndrome protein with poly-ADP ribosyl transferase. FEBS Lett 2003; 554:55–58.CrossRefGoogle Scholar
  28. 28.
    Lebel M, Lavoie J, Gaudreault I et al. Genetic cooperation between the Werner syndrome protein and poly(ADP-ribose) polymerase-1 in preventing chromatid breaks, complex chromosomal rearrangements, and cancer in mice. Am J Pathol 2003; 162:1559–1569.PubMedGoogle Scholar
  29. 29.
    von Kobbe C, Harrigan JA, May A et al. Central role for the Werner syndrome protein/poly(ADP-ribose) polymerase 1 complex in the poly(ADP-ribosyl)ation pathway after DNA damage. Mol Cell Biol 2003; 23:8601–8613.CrossRefGoogle Scholar
  30. 30.
    Lebel M, Spillare EA, Harris CC et al. The Werner syndrome gene product copurifies with the DNA replication complex and interacts with PCNA and topoisomerase I. J Biol Chem 1999; 274:37795–37799.PubMedCrossRefGoogle Scholar
  31. 31.
    Li B, Navarro S, Kasahara N et al. Identification and biochemical characterization of a Werner’s syndrome protein complex with Ku70/80 and poly(ADP-ribose) polymerase-1. J Biol Chem 2004; 279:13659–13667.PubMedCrossRefGoogle Scholar
  32. 32.
    Morrison C, Smith GC, Stingl L et al. Genetic interaction between PARP and DNA-PK in V(D)J recombination and tumorigenesis. Nat Genet 1997; 17:479–482.PubMedCrossRefGoogle Scholar
  33. 33.
    Ruscetti T, Lehnert BE, Halbrook J et al. Stimulation of the DNA-dependent protein kinase by poly(ADP-ribose) polymerase. J Biol Chem 1998; 273:14461–14467.PubMedCrossRefGoogle Scholar
  34. 34.
    Ariumi Y, Masutani M, Copeland TD et al. Suppression of the poly(ADP-ribose) polymerase activity by DNA-dependent protein kinase in vitro. Oncogene 1999; 18:4616–4625.PubMedCrossRefGoogle Scholar
  35. 35.
    Henrie MS, Kurimasa A, Burma S et al. Lethality in PARP/Ku80 double mutant mice reveals physiological synergy during early embryogenesis. DNA Repair 2003; 2:151–158.PubMedCrossRefGoogle Scholar
  36. 36.
    Ménissier-de Murcia J, Mark M, Wendling O et al. Early embryonic lethality in PARP-1 Atm double-mutant mice suggests a functional synergy in cell proliferation during development. Mol Cell Biol 2001; 21:1828–1832.CrossRefGoogle Scholar
  37. 37.
    Marecki JC, McCord JM. The inhibition of poly(ADP-ribose) polymerase enhances growth rates of ataxia telangiectasia cells. Arch Biochem Biophys 2002; 402:227–234.PubMedCrossRefGoogle Scholar
  38. 38.
    Krishna TSR, Kong X-P, Gary S et al. Crystal structure of the eukaryotic DNA polymerase processivity factor PCNA. Cell 1994; 79:1233–1243.PubMedCrossRefGoogle Scholar
  39. 39.
    Kelman Z, Hurwitz J. Protein-PCNA interactions: A DNA scanning mechanism? Trends Biochem Sci 1998; 23:236–238.PubMedCrossRefGoogle Scholar
  40. 40.
    Maga G, Hübscher U. Proliferating cell nuclear antigen (PCNA): A dancer with many partners. J Cell Sci 2003; 116:3051–3060.PubMedCrossRefGoogle Scholar
  41. 41.
    Chapados BR, Hosfield DJ, Han S et al. Structural basis for FEN-1 substrate specificity and PCNA-mediated activation in DNA replication and repair. Cell 2004; 116:39–50.PubMedCrossRefGoogle Scholar
  42. 42.
    Levin DS, Bai W, Yao N et al. An interaction between DNA ligase I and proliferating cell nuclear antigen: Implications for Okazaki fragment synthesis and rejoining. Proc Natl Acad Sci USA 1997; 94:12863–12868.PubMedCrossRefGoogle Scholar
  43. 43.
    Waga S, Stillman B. The DNA replication fork in eukaryotic cells. Annu Rev Biochem 1998; 67:721–751.PubMedCrossRefGoogle Scholar
  44. 44.
    Shibahara K, Stillman B. Replication-dependent marking of DNA by PCNA facilitates CAF-1-coupled inheritance of chromatin. Cell 1999; 96:575–585.PubMedCrossRefGoogle Scholar
  45. 45.
    Chuang LS-H, Ian H-I, Koh T-W et al. Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. Science 1997; 277:1996–2000.PubMedCrossRefGoogle Scholar
  46. 46.
    Zardo G, Reale A, Passananti C et al. Inhibition of poly(ADP-ribosyl)ation induces DNA hypermethylation: A possible molecular mechanism. FASEB J 2002; 16:1319–1321.PubMedGoogle Scholar
  47. 47.
    Kleczkowska HE, Marra G, Lettieri T et al. hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci. Genes Dev 2001; 15:724–736.PubMedCrossRefGoogle Scholar
  48. 48.
    Otterlei E Warbrick TA, Nagelhus T et al. Post-replicative base excision repair in replication foci. EMBO J 1999; 18:3834–3844.PubMedCrossRefGoogle Scholar
  49. 49.
    Muller-Weeks SJ, Caradonna S. Specific association of cyclin-like uracil-DNA glycosylase with the proliferating cell nuclear antigen. Exp Cell Res 1996; 226:346–355.PubMedCrossRefGoogle Scholar
  50. 50.
    Kedar PS, Kim SJ, Robertson A et al. Direct interaction between mammalian DNA polymerase β and proliferating cell nuclear antigen. J Biol Chem 2002; 277:31115–31123.PubMedCrossRefGoogle Scholar
  51. 51.
    Haracska L, Johnson RE, Unk I et al. Physical and functional interaction of human DNA polymerase η with PCNA. Mol Cell Biol 2001; 21:7199–7206.PubMedCrossRefGoogle Scholar
  52. 52.
    Haracska L, Johnson RE, Unk I et al. Targeting of human DNA polymerase ι to the replication machinery via interaction with PCNA. Proc Natl Acad Sci USA 2001; 98:14256–14261.PubMedCrossRefGoogle Scholar
  53. 53.
    Haracska L, Johnson RE, Unk I et al. Stimulation of DNA synthesis activity of human DNA polymerase κ by PCNA. Mol Cell Biol 2002; 22:784–791.PubMedCrossRefGoogle Scholar
  54. 54.
    Maga G, Villani G, Ramadan K et al. Human DNA polymerase λ functionally and physically interacts with proliferating cell nuclear antigen in normal and translesion DNA synthesis. J Biol Chem 2002; 277:48434–48440.PubMedCrossRefGoogle Scholar
  55. 55.
    Ibe S, Fujita K, Toyomoto T et al. Terminal deoxynucleotidyltransferase is negatively regulated by direct interaction with proliferating cell nuclear antigen. Genes Cells 2001; 6:815–824.PubMedCrossRefGoogle Scholar
  56. 56.
    Dianova II, Bohr VA, Dianov GL. Interaction of human AP endonuclease 1 with flap endonuclease 1 and proliferating cell nuclear antigen involved in long-patch base excision repair. Biochemistry 2001; 40:12639–12644.PubMedCrossRefGoogle Scholar
  57. 57.
    Tsuchimoto D, Sakai Y, Sakumi K et al. Human APE2 protein is mostly localized in the nuclei and to some extent in the mitochondria, while nuclear APE2 is partly associated with proliferating cell nuclear antigen. Nucl Acids Res 2001; 29:2349–2360.PubMedCrossRefGoogle Scholar
  58. 58.
    Parker A, Gu Y, Mahoney W et al. Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long patch DNA base excision repair. J Biol Chem 2001; 276:5547–5555.PubMedCrossRefGoogle Scholar
  59. 59.
    Ise T, Nagatani G, Imamura T et al. Transcription factor Y-box binding protein 1 binds preferentially to cisplatin-modified DNA and interacts with proliferating cell nuclear antigen. Cancer Res 1999; 59:342–346.PubMedGoogle Scholar
  60. 60.
    Hasan S, Hassa PO, Imhof R et al. Transcription coactivator p300 binds PCNA and may have a role in DNA repair synthesis. Nature 2001; 410:387–391.PubMedCrossRefGoogle Scholar
  61. 61.
    Milutinovic S, Zhuang Q, Szyf M. Proliferating cell nuclear antigen associates with histone deacetylase activity, integrating DNA replication and chromatin modification. J Biol Chem 2002; 277:20974–20978.PubMedCrossRefGoogle Scholar
  62. 62.
    Fujise K, Zhang D, Liu J et al. Regulation of apoptosis and cell cycle progression by MCL1. Differential role of proliferating cell nuclear antigen. J Biol Chem 2000; 275:39458–39465.PubMedCrossRefGoogle Scholar
  63. 63.
    Scott M, Bonnefin P, Vieyra D et al. UV-induced binding of ING1 to PCNA regulates the induction of apoptosis. J Cell Sci 2001; 114:3455–3462.PubMedGoogle Scholar
  64. 64.
    Ando T, Kawabe T, Ohara H et al. Involvement of the interaction between p21 and proliferating cell nuclear antigen for the maintenance of G2/M arrest after DNA damage. J Biol Chem 2001; 276:42971–42977.PubMedCrossRefGoogle Scholar
  65. 65.
    Ohta S, Shiomi Y, Sugimoto K et al. A proteomic approach to identify proliferating cell nuclear antigen (PCNA)-binding proteins in human cell lysates. J Biol Chem 2002; 277:40362–40367.PubMedCrossRefGoogle Scholar
  66. 66.
    Schmidt KH, Derry KL, Kolodner RD. Saccharomyces cerevisiae RRM3, a 5′ to 3′ DNA helicase, physically interacts with proliferating cell nuclear antigen. J Biol Chem 2002; 277:45331–45337.PubMedCrossRefGoogle Scholar
  67. 67.
    Warbrick E. PCNA binding through a conserved motif. BioEssays 1998; 20:195–199.PubMedCrossRefGoogle Scholar
  68. 68.
    Riva F, Savio M, Cazzalini O et al. Distinct pools of proliferating cell nuclear antigen associated to DNA replication sites interact with p125 subunit of DNA polymerase δ or DNA ligase I. Exp Cell Res 2004; 293:357–367.PubMedCrossRefGoogle Scholar
  69. 69.
    Prosperi E. Multiple roles of the proliferating cell nuclear antigen: DNA replication, repair, and cell cycle control. In: Meijer L, Guidet S, Philippe M, eds. Progress in Cell Cycle Research, Vol. 3. New York: Plenum Press, 1997:193–210.Google Scholar
  70. 70.
    Stivala LA, Riva F, Cazzalini O et al. p21waf1/cip1-null human fibroblasts are deficient in nucleotide excision repair downstream the recruitment of PCNA to DNA repair sites. Oncogene 2001; 20:563–570.PubMedCrossRefGoogle Scholar
  71. 71.
    Dotto GP. p 21WAF1/Cip1: More than a break to the cell cycle? Biochim Biophys Acta 2000; 1471:M43–M46.PubMedGoogle Scholar
  72. 72.
    Coqueret O. New roles for p 21 and p27 cell-cycle inhibitors: A function for each cell compartment? Trends Cell Biol 2003; 13:65–70.PubMedCrossRefGoogle Scholar
  73. 73.
    Chen J, Jackson PK, Kirschner MW et al. Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA. Nature 1995; 374:386–388.PubMedCrossRefGoogle Scholar
  74. 74.
    Luo Y, Hurwitz J, Massague J. Cell-cycle inhibition by independent CDK and PCNA binding domains in p21Cip1. Nature 1995; 375:159–161.PubMedCrossRefGoogle Scholar
  75. 75.
    Warbrick E, Lane DP, Glover DM et al. Homologous regions of Fen1 and p21Cip1 compete for binding to the same site on PCNA: A potential mechanism to coordinate DNA replication and repair. Oncogene 1997; 14:2313–2321.PubMedCrossRefGoogle Scholar
  76. 76.
    Cazzalini O, Perucca P, Riva F et al. p21CDKN1A does not interfere with loading of PCNA at DNA replication sites, but inhibits subsequent binding of DNA polymerase δ at the G1/Sphase transition. Cell Cycle 2003; 2:596–603.PubMedGoogle Scholar
  77. 77.
    Shivji MK, Ferrari E, Ball K et al. Resistance of human nucleotide excision repair synthesis in vitro to p21Cdn1. Oncogene 1998; 17:2827–2838.PubMedCrossRefGoogle Scholar
  78. 78.
    Savio M, Stivala LA, Scovassi AI et al. p21waf1/cip1 protein associates with the detergent-insoluble form of PCNA concomitantly with disassembly of PCNA at nucleotide excision repair sites. Oncogene 1996; 13:1591–1598.PubMedGoogle Scholar
  79. 79.
    McDonald III ER, Wu GS, Waldman T et al. Repair defect in p21WAF1/CIP1-/- human cancer cells. Cancer Res 1996; 56:2250–2255.PubMedGoogle Scholar
  80. 80.
    Sheikh MS, Chen YQ, Smith ML et al. Role of p21waf1/cip1/sdi1 in cell death and DNA repair as studied using a tetracycline-inducible system in p53-deficient cells. Oncogene 1997; 14:1875–1882.PubMedCrossRefGoogle Scholar
  81. 81.
    Frouin I, Maga G, Denegri M et al. Human proliferating cell nuclear antigen, poly(ADP-ribose) polymerase-1 and p21waf1/cip1: A dynamic exchange of partners. J Biol Chem 2003; 278:39265–39268.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2006

Authors and Affiliations

  • Ennio Prosperi
    • 1
  • A. Ivana Scovassi
    • 1
  1. 1.Istituto di Genetica Molecolare CNRPaviaItaly

Personalised recommendations