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Maintenance of the DNA-damage checkpoint requires DNA-damage-induced mediator protein oligomerization.

Oligomeric assembly of Brca1 C-terminal (BRCT) domain-containing mediator proteins occurs at sites of DNA damage. However, the functional significance and regulation of such assemblies are not well understood. In this study, we defined the molecular mechanism of DNA-damage-induced oligomerization of the S. cerevisiae BRCT protein Rad9. Our data suggest that Rad9's tandem BRCT domain mediates Rad9 oligomerization via its interaction with its own Mec1/Tel1-phosphorylated SQ/TQ cluster domain (SCD). Rad53 activation is unaffected by mutations that impair Rad9 oligomerization, but checkpoint maintenance is lost, indicating that oligomerization is required to sustain checkpoint signaling. Once activated, Rad53 phosphorylates the Rad9 BRCT domain, which attenuates the BRCT-SCD interaction. Failure to phosphorylate the Rad9 BRCT results in cytologically visible Rad9 foci. This suggests a feedback loop wherein Rad53 activity and Rad9 oligomerization are regulated to tune the DNA-damage response.

Pubmed ID: 19187758

Authors

  • Usui T
  • Foster SS
  • Petrini JH

Journal

Molecular cell

Publication Data

January 30, 2009

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM56888
  • Agency: NIGMS NIH HHS, Id: GM59413
  • Agency: NCI NIH HHS, Id: P30 CA08748
  • Agency: NIGMS NIH HHS, Id: R01 GM056888
  • Agency: NIGMS NIH HHS, Id: R01 GM056888-12
  • Agency: NIGMS NIH HHS, Id: R01 GM059413
  • Agency: NIGMS NIH HHS, Id: R01 GM059413-12

Mesh Terms

  • Binding Sites
  • Cell Cycle Proteins
  • Checkpoint Kinase 2
  • DNA Damage
  • DNA, Fungal
  • Genes, cdc
  • Intracellular Signaling Peptides and Proteins
  • Mutation
  • Phosphorylation
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • Saccharomyces cerevisiae Proteins
  • Signal Transduction