Effects of PARP1 and PARG inhibition on the Unfolded Protein Response in Glioblastoma

Glioblastoma (GBM) is the most severe form of brain cancer for which there is currently no cure; and the treatment style typically used (chemotherapy and radiation) can be very strenuous on the patient. An interesting avenue for treatment development stems from the unfolded protein response (UPR), a regulatory process that is activated in response to cellular stress and determines cell fate. When activated in cancer, UPR may trigger programmed cell death, essentially making the cancer attack itself. In order to explore the therapeutic interest of targeting UPR, we must better understand this molecular pathway. UPR is known to be affected by a modification named PARylation which consists in the dynamic synthesis and degradation of a polymer of ADP-ribose or PAR by the proteins PARP1 and PARG, respectively. We propose to dissect the mechanism of UPR activation in connection to PARylation. Previously, I observed that upregulation of PARylation for a short period of time or downregulation of PARylation for a long period of time could be an activator of UPR, suggesting that PAR modulates UPR via different modes. Using biochemical and cellular approaches and inhibitors of PARP1 and PARG, I will analyze these new regulatory modes of UPR. By evaluating the functional link between PARylation and UPR, novel therapeutic possibilities may arise for GBM.