Figure 6.

Proposed mechanism for the regulation of RRM2 levels by the ATR-CHK1 and WEE1 pathways in Ewing sarcoma cells. Inhibition of the ATR-CHK1 and WEE1 pathways in Ewing sarcoma cells experiencing DNA replication stress, caused by inhibition of RRM1, RRM2, or other mechanisms, leads to the aberrant activation of CDK2. Active CDK2, in turn, phosphorylates and targets RRM2 for degradation via the proteasome. This reduction in the level of the RRM2 protein caused by activation of CDK2 generates a feedback loop which exacerbates DNA replication stress, increases DNA damage, and induces apoptosis.