Figure 5.

General model for the involvement of c-Abl in the DNA damage response and in regulation of DSB repair. (a) c-Abl regulates programmed cell death and DSB repair in response to DNA damage. c-Abl is activated in the context of the DNA damage response. It phosphorylates p73⁹ and Yap1¹² and activates the p73-dependent cell death response (right panel). c-Abl also interacts with various components of DSB repair, some of which are phosphorylated by it and some of which phosphorylate c-Abl (left panel). c-Abl interacts with ATM and this interaction is likely to be involved in the activation of c-Abl.^{13, 14} c-Abl associates with DNA-PK resulting in a potential reciprocal phosphorylation and interacts also with the Ku80 protein.¹⁵ c-Abl associates with and regulates the activity of Rad51,¹⁶ Rad52,¹⁷ WRN¹⁸ as well as BRCA1.¹⁹ The data presented herein indicate that activated c-Abl functionally downregulates DSB repair. The potential mechanism by which this downregulation occurs incorporates the various interactions of c-Abl with proteins involved in DSB repair. (b) According to our results c-Abl-mediated downregulation of DSB repair is most dominant during slow-phase DSB repair. This time-dependent pattern of repair downregulation follows the time-dependent increase in c-Abl activation in response to DNA damage and correlates with the time frame within which DSB repair is most likely to be error-prone