The DNA damage response mediator MDC1 directly interacts with the anaphase-promoting complex/cyclosome.

MDC1 (NFBD1), a mediator of the cellular response to DNA damage, plays an important role in checkpoint activation and DNA repair. Here we identified a cross-talk between the DNA damage response and cell cycle regulation. We discovered that MDC1 binds the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that controls ...
the cell cycle. The interaction is direct and is mediated by the tandem BRCA1 C-terminal domains of MDC1 and the C terminus of the Cdc27 (APC3) subunit of the APC/C. It requires the phosphorylation of Cdc27 and is enhanced after induction of DNA damage. We show that the tandem BRCA1 C-terminal domains of MDC1, known to directly bind the phosphorylated form of histone H2AX (gamma-H2AX), also bind the APC/C by the same mechanism, as phosphopeptides that correspond to the C termini of gamma-H2AX and Cdc27 competed with each other for the binding to MDC1. Our results reveal a link between the cellular response to DNA damage and cell cycle regulation, suggesting that MDC1, known to have a role in checkpoint regulation, executes part of this role by binding the APC/C.
Mesh Terms:
Amino Acid Sequence, Cell Cycle, Cell Cycle Proteins, Cell Line, DNA-Binding Proteins, Molecular Sequence Data, Nuclear Proteins, Phosphorylation, Protein Interaction Domains and Motifs, Protein Structure, Tertiary, Radiation, Ionizing, Trans-Activators, Ubiquitin-Protein Ligase Complexes
J. Biol. Chem.
Date: Nov. 02, 2007
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