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Molecular mechanism of poly(ADP-ribosyl)ation by PARP1 and identification of lysine residues as ADP-ribose acceptor sites

Altmeyer, Matthias ; Messner, Simon ; Hassa, Paul O. ; Fey, Monika ; Hottiger, Michael O.

In: Nucleic Acids Research, 2009, vol. 37, no. 11, p. 3723-3738

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    Titre
    • Molecular mechanism of poly(ADP-ribosyl)ation by PARP1 and identification of lysine residues as ADP-ribose acceptor sites
    Auteur
    • Altmeyer, Matthias. Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland, Life Science Zurich Graduate School, Molecular Life Science Program, University of Zurich and European Molecular Biology Laboratory (EMBL), Gene Expression Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany
    • Messner, Simon. Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland, Life Science Zurich Graduate School, Molecular Life Science Program, University of Zurich and European Molecular Biology Laboratory (EMBL), Gene Expression Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany
    • Hassa, Paul O.. Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland, Life Science Zurich Graduate School, Molecular Life Science Program, University of Zurich and European Molecular Biology Laboratory (EMBL), Gene Expression Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany
    • Fey, Monika. Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland, Life Science Zurich Graduate School, Molecular Life Science Program, University of Zurich and European Molecular Biology Laboratory (EMBL), Gene Expression Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany
    • Hottiger, Michael O.. Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland, Life Science Zurich Graduate School, Molecular Life Science Program, University of Zurich and European Molecular Biology Laboratory (EMBL), Gene Expression Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Nucleic Acids Research, 2009, vol. 37, no. 11, p. 3723-3738. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:298582
    Summary
    Poly(ADP-ribose) polymerase 1 (PARP1) synthesizes poly(ADP-ribose) (PAR) using nicotinamide adenine dinucleotide (NAD) as a substrate. Despite intensive research on the cellular functions of PARP1, the molecular mechanism of PAR formation has not been comprehensively understood. In this study, we elucidate the molecular mechanisms of poly(ADP-ribosyl)ation and identify PAR acceptor sites. Generation of different chimera proteins revealed that the amino-terminal domains of PARP1, PARP2 and PARP3 cooperate tightly with their corresponding catalytic domains. The DNA-dependent interaction between the amino-terminal DNA-binding domain and the catalytic domain of PARP1 increased Vmax and decreased the Km for NAD. Furthermore, we show that glutamic acid residues in the auto-modification domain of PARP1 are not required for PAR formation. Instead, we identify individual lysine residues as acceptor sites for ADP-ribosylation. Together, our findings provide novel mechanistic insights into PAR synthesis with significant relevance for the different biological functions of PARP family members