Summary of the mechanistic findings presented in this paper. The ATM and FA pathways (white boxes/arrows) are two DNA damage response pathways that display synthetic lethal relationship. Inhibition of the FA pathway may therefore be used as a targeted therapy to selectively kill ATM-deficient tumors. Several enzymatic complexes have been proposed to modulate the FA pathway (light grey boxes). Monitoring the effect of the compounds used in this study (dark grey boxes) toward those enzymatic activities suggests that (i) in contrast with cell-based assays, the proteasome is not required for FA pathway activation in Xenopus extracts, (ii) in contrast with curcumin, EF24 is a weak proteasome inhibitor, (iii) EF24 does not inhibit the FA pathway through disruption of the core complex, and (iv) curcumin, EF24 and BMS-345541 might inhibit the FA pathway through inhibition of IKK.