PARP7-mediated ADP-ribosylation stabilizes FRA1 and restrains IRF3/IRF1-dependent apoptosis and immune signaling and in cancer cells

ABSTRACT: PARP7 inhibitors suppress tumor growth in a cell autonomous manner and by activating the immune system through restoring immune signaling. Nevertheless, the targets of PARP7-mediated ADP-ribosylation that regulate innate immune signaling and cancer cell survival remain elusive. Here, we identified PARP7 as a nuclear and cysteine-specific mono-ADP-ribosyltransferase that modified proteins critical for regulating transcription, such as the AP-1 transcription factor FRA1. Loss of FRA1 ADP-ribosylation via PARP7 inhibition by RBN-2397 or mutation of the ADP-ribosylation site C97 increased FRA1 degradation by PSMC3 and the proteasome. We found that the reduction in FRA1 protein levels promoted IRF3 and IRF1-dependent innate immune signaling and CASP8-mediated apoptosis. Furthermore, we demonstrated that high PARP7 expression are critical for inducing apoptosis in FRA1-positive cancer cells using the PARP7 inhibitor. Collectively, our findings highlight the connected roles of PARP7 and FRA1 and emphasize the clinical potential of PARP7 inhibitors for FRA1-driven cancers.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Lung Endothelial Cell

DISEASE(S): Lung Cancer

SUBMITTER: Deena Leslie Pedrioli  

LAB HEAD: Michael Hottiger

PROVIDER: PXD041870 | Pride | 2024-01-26

REPOSITORIES: Pride