Description:
<jats:p>Disruption of <jats:italic>Brca1</jats:italic> results in cellular demise or tumorigenesis depending on cellular context. Inactivation of p53 contributes to <jats:italic>Brca1</jats:italic>-associated tumor susceptibility. However the activation of p53-dependent checkpoint/apoptotic signaling in the absence of <jats:italic>Brca1</jats:italic> is poorly understood. Here, we show that <jats:italic>Chk2</jats:italic> inactivation is partially equivalent to p53 inactivation, in that Chk2 deficiency facilitates the development, survival, and proliferation of Brca1-deficient T cells at the expense of genomic integrity. Brca1 deficiency was found to result in Chk2 phosphorylation and the Chk2-dependent accumulation and activation of p53. Furthermore, inactivation of <jats:italic>Chk2</jats:italic> and <jats:italic>Brca1</jats:italic> was cooperative in breast cancer. Our findings identify a critical role for Chk2 as a component of the DNA damage-signaling pathway activated in response to Brca1 deficiency.</jats:p>