Scientific article

Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation

Published inMolecular and cellular biology, vol. 22, no. 12, p. 4020-4032
Publication date2002

BRCA1 plays an important role in mechanisms of response to double-strand breaks, participating in genome surveillance, DNA repair, and cell cycle checkpoint arrests. Here, we identify a constitutive BRCA1-c-Abl complex and provide evidence for a direct interaction between the PXXP motif in the C terminus of BRCA1 and the SH3 domain of c-Abl. Following exposure to ionizing radiation (IR), the BRCA1-c-Abl complex is disrupted in an ATM-dependent manner, which correlates temporally with ATM-dependent phosphorylation of BRCA1 and ATM-dependent enhancement of the tyrosine kinase activity of c-Abl. The BRCA1-c-Abl interaction is affected by radiation-induced modification to both BRCA1 and c-Abl. We show that the C terminus of BRCA1 is phosphorylated by c-Abl in vitro. In vivo, BRCA1 is phosphorylated at tyrosine residues in an ATM-dependent, radiation-dependent manner. Tyrosine phosphorylation of BRCA1, however, is not required for the disruption of the BRCA1-c-Abl complex. BRCA1-mutated cells exhibit constitutively high c-Abl kinase activity that is not further increased on exposure to IR. We suggest a model in which BRCA1 acts in concert with ATM to regulate c-Abl tyrosine kinase activity.

  • BRCA1 Protein/genetics/metabolism/radiation effects
  • Binding Sites
  • Cell Cycle Proteins
  • Cells, Cultured
  • DNA-Binding Proteins
  • Humans
  • Mutation
  • Phosphorylation
  • Protein-Serine-Threonine Kinases/genetics/metabolism/radiation effects
  • Proto-Oncogene Proteins c-abl/genetics/metabolism/radiation effects
  • Radiation, Ionizing
  • Tumor Suppressor Proteins
Citation (ISO format)
FORAY, Nicolas et al. Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation. In: Molecular and cellular biology, 2002, vol. 22, n° 12, p. 4020–4032. doi: 10.1128/mcb.22.12.4020-4032.2002
Main files (1)
Article (Published version)
ISSN of the journal0270-7306

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