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
复制标题
DOI：
10.1128/mcb.22.12.4020-4032.2002
复制
发表时间：
2002-06-01
影响因子：
5.3
通讯作者：
Jeggo, P
中科院分区：
文献类型：
--
作者：
Foray, N;Marot, D;Jeggo, P
BRCA1 在双链断裂反应机制中发挥着重要作用，参与基因组监测、DNA 修复和细胞周期检查点停滞。在这里，我们鉴定了一个组成型 BRCA1-c-Abl 复合物，并为 BRCA1 C 末端的 PXXP 基序与 c-Abl 的 SH3 结构域之间的直接相互作用提供了证据。暴露于电离辐射后 (111)，BRCA1-c-Abl 复合物以 ATM 依赖性方式被破坏，这与 BRCA1 的 ATM 依赖性磷酸化和 c-Abl 酪氨酸激酶活性的 ATM 依赖性增强在时间上相关。 BRCA1-c-Abl 相互作用受到辐射诱导的 BRCA1 和 c-Abl 修饰的影响。我们发现 BRCA1 的 C 末端在体外被 c-Abl 磷酸化。在体内，BRCA1 在酪氨酸残基处以 ATM 依赖性、辐射依赖性方式磷酸化。然而，BRCA1 的酪氨酸磷酸化并不是破坏 BRCA1-c-Abl 复合物所必需的。 BRCA1 突变细胞表现出持续高的 c-Ab1 激酶活性，且在暴露于 IR 后不会进一步增加。我们提出了一种模型，其中 BRCA1 与 ATM 协同作用来调节 c-Abl 酪氨酸激酶活性。
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 (111), 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-Ab1 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.