title: The molecular basis of ATM-dependent dimerization of the Mdc1 DNA damage checkpoint mediator.
abstract: 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.
authors.affiliation: Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jungmichel
authors.forename: Julie A
authors.initials: JA
authors.lastname: Clapperton
authors.forename: Janette
authors.initials: J
authors.lastname: Lloyd
authors.forename: Flurina J
authors.initials: FJ
authors.lastname: Hari
authors.forename: Christoph
authors.initials: C
authors.lastname: Spycher
authors.forename: Lucijana
authors.initials: L
authors.lastname: Pavic
authors.forename: Jiejin
authors.initials: J
authors.lastname: Li
authors.forename: Lesley F
authors.initials: LF
authors.lastname: Haire
authors.forename: Mario
authors.initials: M
authors.lastname: Bonalli
authors.forename: Dorthe H
authors.initials: DH
authors.lastname: Larsen
authors.forename: Claudia
authors.initials: C
authors.lastname: Lukas
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
authors.forename: Derek
authors.initials: D
authors.lastname: MacMillan
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nielsen
authors.forename: Manuel
authors.initials: M
authors.lastname: Stucki
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Smerdon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D010769:Phosphothreonine / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C413163:MDC1 protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; C498302:Trp53bp1 protein, mouse; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; D010769:Phosphothreonine; D013912:Threonine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases