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Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation.
Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2002 Jun; Vol. 22 (12), pp. 4020-32. - Publication Year :
- 2002
-
Abstract
- 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.
- Subjects :
- Ataxia Telangiectasia Mutated Proteins
BRCA1 Protein genetics
Binding Sites
Cell Cycle Proteins
Cells, Cultured
DNA-Binding Proteins
Humans
Mutation
Phosphorylation
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases radiation effects
Proto-Oncogene Proteins c-abl genetics
Proto-Oncogene Proteins c-abl radiation effects
Radiation, Ionizing
Tumor Suppressor Proteins
BRCA1 Protein metabolism
BRCA1 Protein radiation effects
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins c-abl metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0270-7306
- Volume :
- 22
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 12024016
- Full Text :
- https://doi.org/10.1128/MCB.22.12.4020-4032.2002