The molecular basis of ATM-dependent dimerization of the Mdc1 DNA damage checkpoint mediator |
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Authors: | 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 |
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Institution: | Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich - Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. |
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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. |
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