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

Foray, Nicolas
Marot, Didier
Randrianarison, Voahangy
Venezia, Nicole Dalla
Perricaudet, Michel
Favaudon, Vincent
Jeggo, Penny
Published in Molecular and cellular biology. 2002, vol. 22, no. 12, p. 4020-32
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.
Keywords BRCA1 Protein/genetics/metabolism/radiation effectsBinding SitesCell Cycle ProteinsCells, CulturedDNA-Binding ProteinsHumansMutationPhosphorylationProtein-Serine-Threonine Kinases/genetics/metabolism/radiation effectsProto-Oncogene Proteins c-abl/genetics/metabolism/radiation effectsRadiation, IonizingTumor Suppressor Proteins
PMID: 12024016
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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. 4020-32. doi: 10.1128/mcb.22.12.4020-4032.2002 https://archive-ouverte.unige.ch/unige:4626

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Deposited on : 2009-12-07

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