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

J Biol Chem. 2007 Nov 2;282(44):32053-64. doi: 10.1074/jbc.M705890200. Epub 2007 Sep 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anaphase-Promoting Complex-Cyclosome
  • Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • Cell Cycle*
  • Cell Line
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism
  • Molecular Sequence Data
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Protein Interaction Domains and Motifs
  • Protein Structure, Tertiary
  • Radiation, Ionizing
  • Trans-Activators / chemistry
  • Trans-Activators / metabolism*
  • Ubiquitin-Protein Ligase Complexes / metabolism*

Substances

  • Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome
  • CDC27 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • MDC1 protein, human
  • Nuclear Proteins
  • Trans-Activators
  • Ubiquitin-Protein Ligase Complexes
  • Anaphase-Promoting Complex-Cyclosome