Abstract
A dual approach to the study of poly (ADP-ribose)polymerase (PARP) in terms of its structure and function has been developed in our laboratory. Random mutagenesis of the DNA binding domain and catalytic domain of the human PARP, has allowed us to identify residues that are crucial for its enzymatic activity.
In parallel PARP knock-out mice were generated by inactivation of both alleles by gene targeting. We showed that: (i) they are exquisitely sensitive to γ-irradiation, (ii) they died rapidly from acute radiation toxicity to the small intestine, (iii) they displayed a high genomic instability to γ-irradiation and MNU injection and, (iv) bone marrow cells rapidly underwent apoptosis following MNU treatment, demonstrating that PARP is a survival factor playing an essential and positive role during DNA damage recovery and survival.
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Trucco C, Flatter E, Fribourg S, de Murcia C, and Ménissier-de Murcia J: Mutations in the amino-terminal domain of the human poly(ADP-ribose) polymerase that affect its catalytic activity but not its DNA binding capacity. FEBS Lett 399: 313–316, 1996
Rolli V, O’Farrell M, Ménissier-de Murcia J, de Murcia C: Random mutagenesis of the poly(ADP-ribose) polymerase catalytic domain reveals amino acids involved in polymer branching. Biochemistry 36: 12147–12154, 1997
Ménissier-de Murcia J, Niedergang C, Trucco C, Ricoul M, Dutrillaux B, Mark M, Olivier FJ, Masson M, Dierich A, LeMeur M, Walztinger C, Chambon P, de Murcia C: Requirement of poly(ADPribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci USA 94: 7303–7307, 1997
Ménissier de Murcia J, Molinete M, Gradwohl G, Simonin F, de Murcia G: Zinc-binding domain of poly(ADP-ribose)polymerase participates in the recognition of single strand breaks on DNA. J Mol Biol 210: 229–233, 1989
Schreiber V, Molinete M, Boeuf H, de Murcia G, Ménissier-de Murcia J: The human poly(ADP-ribose) polymerase nuclear localization signal is a bipartite element functionally separate from DNA binding and catalytic activity. EMBO J 11: 3263–2369, 1992
Simonin F, Ménissier-de Murcia J, Poch O, Muller S, Gradwohl G, Molinete M, Penning C, Keith G, de Murcia G: Expression and site-directed mutagenesis of the catalytic domain of human poly(ADP-ribose)polymerase in Escherichia coli. Lysine 893 is critical for activity. J Biol Chem 265: 19249–19256, 1990
Gradwohl G, Ménissier-de Murcia J, Molinete M, Simonin F, Koken M, Hoeijmakers JH, de Murcia G: The second zinc-finger domain of poly(ADP-ribose) polymerase determines specificity for singlestranded breaks in DNA. Proc Natl Acad Sci USA 87: 2990–2994, 1990
Ikejima M, Noguchi S, Yamashita R, Ogura T, Sugimura T, Gill DM, Miwa M: The zinc fingers of human poly(ADP-ribose) polymerase are differentially required for the recognition of DNA breaks and nicks and the consequent enzyme activation. Other structures recognize intact DNA. J Biol Chem 265: 21907–21913, 1990
Molinete M, Vermeulen W, Burkle A, Ménissier-de Murcia J, Kupper JH, Hoeijmakers JH, de Murcia G: Overproduction of the poly(ADP-ribose) polymerase DNA-binding domain blocks alkylationinduced DNA repair synthesis in mammalian cells. EMBO J 12: 2109–2117, 1993
Griesenbeck J, Oei SL, Mayer-Kuckuk P, Ziegler M, Buchlow G, Schweiger M: Protein-protein interaction of the human poly(ADP-ribose)polymerase depends on the functional state of the enzyme. Biochemistry 36: 7297–7304, 1997
Simonin F, Briand JP, Möller S, de Murcia G: Detection of poly(ADP-ribose) polymerase in crude extracts by activity-blot. Anal Biochem 195: 226–231, 1991
de Murcia C, Ménissier-de Murcia J: Poly(ADP-ribose) polymerase: A molecular nick-sensor. Trends Biochem Sci 19: 172–176, 1994
Marsischky CT, Wilson BA, Collier RJ: Role of glutamic acid 988 of human poly-ADP-ribose polymerase in polymer formation. Evidence for active site similarities to the ADP-ribosylating toxins. J Biol Chem 270: 3247–3254, 1995
Keith G, Desgres J, de Murcia G: Use of two-dimensional thin-layer chromatography for the components study of poly(adenosine diphosphate ribose). Anal Biochem 191: 309–313, 1990
Jung S, Miranda EA, Ménissier-de Murcia J, Niedergang C, Delarue M, Schulz CE, de Murcia G: Crystallization and X-ray crystallographic analysis of recombinant chicken poly(ADP-ribose) polymerase catalytic domain produced in Sf9 insect cells. J Mol Biol 244: 114–116, 1994
Ruf A, Ménissier-de Murcia J, de Murcia G, Schulz GE: Structure of the catalytic fragment of poly (ADP-ribose)polymerase from chicken. Proc Natl Acad Sci USA 93: 7481–7485, 1996
Kim H, Jacobson MK, Rolli V, Ménissier-de Murcia J, Reinbolt J, Simonin F, Ruf A, Schulz G, de Murcia G: Photoaffinity labelling of human poly(ADP-ribose) polymerase catalytic domain. Biochem J 322: 469–75, 1997
Miranda EA, Dantzer F, O’Farrell M, de Murcia G, Ménissier-de Murcia J: Characterization of a gain-of-function mutant of poly(ADP-ribose) polymerase. Biochem Biophys Res Commun 212: 317–325, 1995
Wang ZQ, Auer B, Stingl L, Berghammer H, Haidacher D, Schweiger M, Wagner EW: Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease. Genes Dev 9: 509–520, 1995
Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shilo Y, Crawley JN, Ried T, Tagle D, Wynshaw-Boris A: Atm-deficient mice: A paradigm of ataxia telangectasia. Cell 86: 159–171, 1996
Biedermann KA, Sun J, Giaccia AJ, Tosto LM, Brown JM: scid mutation in mice confers hypersensivity to ionizing radiation and a deficiency in DNA double-strand break repair. Proc Natl Acad Sci 88: 1394–1397, 1991
Schreiber V, Hunting D, Trueco C, Gowans B, Crunwald D, de Murcia G, Ménissier-de Murcia J: A dominant-negative mutant of human poly(ADP-ribose) polymerase affects cell recovery, apoptosis, and sister chromatid exchange following DNA damage. Proc Nati Acad Sci USA 92: 4753–1757, 1995
Oikawa A, Tohda H, Kanai M, Miwa M, Sugimura T: Inhibitors of poly(adenosine diphosphate ribose) polymerase induce sister chromatid exchanges. Biochem Biophys Res Comm 97: 1311–1316, 1980
Tewari M, Quan LT, O’Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirier CC, Salvesen CS, Dixit VM: Yama/CPP32β, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 81: 801–809, 1995
Leist M, Single B, Könstle G, Volbracht C, Hentze H, Nicotera P: Apoptosis in the absence of poly(ADP-ribose) polymerase. Biochem Biophys Res Commun 233: 518–522, 1997
Masson M, Niedergang C, Schreiber V, Ménissier-de Murcia J, de Murcia G: XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol Cell Biol 18: 3563–3571, 1998
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Trucco, C. et al. (1999). A dual approach in the study of poly (ADP-ribose) polymerase: In vitro random mutagenesis and generation of deficient mice. In: Alvarez-Gonzalez, R. (eds) ADP-Ribosylation Reactions: From Bacterial Pathogenesis to Cancer. Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease, vol 30. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8740-2_8
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DOI: https://doi.org/10.1007/978-1-4419-8740-2_8
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