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

Foray, N., Marot, D., Randrianarison, V., Venezia, N. D., Picard, D., Perricaudet, M., Favaudon, V. and Jeggo, P. (2002) Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation. Molecular and Cellular Biology, 22 (12). 4020-4032.. ISSN 0270-7306

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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.

Item Type: Article
Additional Information: GDSC25
Keywords: BRCA1 Protein/genetics/*metabolism/*radiation effects Binding Sites Cells, Cultured Human Mutation Phosphorylation Protein-Serine-Threonine Kinases/genetics/*metabolism/radiation effects Proto-Oncogene Proteins c-abl/genetics/*metabolism/radiation effects Radiation, Ionizing Support, Non-U.S. Gov't
Schools and Departments: School of Life Sciences
Subjects: Q Science > QM Human anatomy
Depositing User: Gee Wheatley
Date Deposited: 03 May 2007
Last Modified: 08 Mar 2017 05:46
URI: http://sro.sussex.ac.uk/id/eprint/1056
Google Scholar:71 Citations

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