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Molecular and Cellular Biology, June 2002, p. 4020-4032, Vol. 22, No. 12
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.12.4020-4032.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Constitutive Association of BRCA1 and c-Abl and Its ATM-Dependent Disruption after Irradiation

Radiobiologie Cellulaire et Moléculaire, U350 Inserm, Institut Curie, 91405 Orsay,¹ Vectorologie et Transfert de Gènes, CNRS UMR1582, Institut Gustave-Roussy, 94805 Villejuif,³ Génétique et Cancer, CNRS UMR 5641, Université Rockefeller, 69373 Lyon, France,⁴ Genome Damage and Stability Centre, University of Sussex, Falmer, BN1 9RR Brighton, United Kingdom,² Département de Biologie Cellulaire, Université de Genève, 1211 Geneva 4, Switzerland⁵

Received 24 September 2001/ Returned for modification 1 November 2001/ Accepted 5 March 2002

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.

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