Figure 3.

Inactivation of CHKREC nodes in FA mutants promotes CCA and reduces FA cell survival. (A) Double KO simulations of the FAcore and components of the CHKREC (WIP1, CDK1-AurA, PLK1, CDC25, and CycB-CDK1) showing that FA cell division will be blocked since the CycB-CDK1 node cannot be activated, driving the system to a cyclic CCA attractors. Only attractors are shown. Nodes in the simulations are grouped by color according to functional categories: DNA damage in black, DNA repair pathways in blue, Checkpoint in red and CHKREC in green. Inactive nodes are colorless, whereas active nodes are colored according to their functional category. (B) Schematics showing that upon CHKREC inhibition, the division of FA mutant cells with unrepaired DNA damage will be blocked and the cell will remain in a CCA attractor. In biological terms, cell division blockade may drive the cell to senescence or cell dead. (C) Screening of multiple CHKREC chemical inhibitors showing that the FAcore mutant cell line EUFA316+EV (FANCG deficient) is more sensitive to CHKREC inhibition than its corrected counterpart EUFA316+G. Refer to Supplementary Materials S2, S3, to see the trajectories followed by these and other FAcore and FANCD2I double null mutants, respectively, before arriving to an attractor.