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The molecular basis of ATM-dependent dimerization of the Mdc1 DNA damage checkpoint mediator

Jungmichel, Stephanie ; Clapperton, Julie A. ; Lloyd, Janette ; Hari, Flurina J. ; Spycher, Christoph ; Pavic, Lucijana ; Li, Jiejin ; Haire, Lesley F. ; Bonalli, Mario ; Larsen, Dorthe H. ; Lukas, Claudia ; Lukas, Jiri ; MacMillan, Derek ; Nielsen, Michael L. ; Stucki, Manuel ; Smerdon, Stephen J.

In: Nucleic Acids Research, 2012, vol. 40, no. 9, p. 3913-3928

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    Titre
    • The molecular basis of ATM-dependent dimerization of the Mdc1 DNA damage checkpoint mediator
    Auteur
    • Jungmichel, Stephanie. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • Clapperton, Julie A.. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • Lloyd, Janette. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • Hari, Flurina J.. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • Spycher, Christoph. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • Pavic, Lucijana. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • Li, Jiejin. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • Haire, Lesley F.. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • Bonalli, Mario. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • Larsen, Dorthe H.. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • Lukas, Claudia. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • Lukas, Jiri. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • MacMillan, Derek. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • Nielsen, Michael L.. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • Stucki, Manuel. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    • Smerdon, Stephen J.. Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Department of Chemistry, University College, London WC1H 0AJ, UK and Department of Proteomics, The Novo-Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Biegdamsvej 3B DK-2200, Copenhagen, Denmark
    Type de document
    • Postprint
    Langue
    • Inglese
    Publié dans
    • Nucleic Acids Research, 2012, vol. 40, no. 9, p. 3913-3928. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:290070
    Summary
    Mdc1 is a large modular phosphoprotein scaffold that maintains signaling and repair complexes at double-stranded DNA break sites. Mdc1 is anchored to damaged chromatin through interaction of its C-terminal BRCT-repeat domain with the tail of γH2AX following DNA damage, but the role of the N-terminal forkhead-associated (FHA) domain remains unclear. We show that a major binding target of the Mdc1 FHA domain is a previously unidentified DNA damage and ATM-dependent phosphorylation site near the N-terminus of Mdc1 itself. Binding to this motif stabilizes a weak self-association of the FHA domain to form a tight dimer. X-ray structures of free and complexed Mdc1 FHA domain reveal a ‘head-to-tail' dimerization mechanism that is closely related to that seen in pre-activated forms of the Chk2 DNA damage kinase, and which both positively and negatively influences Mdc1 FHA domain-mediated interactions in human cells prior to and following DNA damage