Figure 3.

PP2A exerts regulatory activity against multiple substrates within the DNA damage response (DDR) pathways. Shown is a simplified schematic of reported PP2A targets; a complete picture of PP2A’s role would involve added timing and contextual dynamics. Critically, PP2A activity against ATM and Chk1 / Chk2 promotes the high-integrity homologous recombination (HR) repair of damaged DNA and resolution of γH2AX foci marking sites of DNA strand break. In parallel, cell cycle progression is halted due to PP2A inhibition of MDM2 / activation of p53, as well as PP2A activity against PLK1, Aurora Kinase A (AurA), Wee1, and cdc25 that altogether inhibits CDK1/CyclinB. (A) In the face of significant DNA damage induced by radiation or a chemotherapeutic compound, PP2A inhibition impairs damage response and repair, and appropriate cell cycle arrest. Damage persists and cells that attempt to divide experience mitotic catastrophe due to a lethal loss of genome integrity. (B) Similar to BRCA1/2, PP2A has multiple key roles in facilitating HR repair that may allow it to be a candidate for synthetic lethality when its inactivation is coupled with PARP inhibition.