Journal
NUCLEIC ACIDS RESEARCH
Volume 40, Issue 9, Pages 3913-3928Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkr1300
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Funding
- Novo Nordisk Foundation Center for Protein Research
- European Commission [INFRASTRUCTURES-F7-2010-262067/PRIME-XS]
- Danish Cancer Society
- Danish National Research Foundation
- Danish Medical research Council
- Swiss National Foundation [3100A0-111818, 31003A-127450]
- UBS AG (Im Auftrag eines Kunden)
- Kanton of Zurich
- Medical Research Council, UK [U117584228]
- MRC, UK
- Swiss National Science Foundation (SNF) [31003A_127450] Funding Source: Swiss National Science Foundation (SNF)
- MRC [MC_U117584228] Funding Source: UKRI
- Medical Research Council [MC_U117584228] Funding Source: researchfish
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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 gamma H2AX 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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