PARP7-mediated ADP-ribosylation of FRA1 promotes cancer cell growth by repressing IRF1- and IRF3-dependent apoptosis

• DOI: 10.1073/pnas.2309047120
• Publication Date: 2023-11-27T20:22:27Z
• Authors: Patrick Manetsch; Flurina Böhi; Kathrin Nowak; Deena M. Leslie P...; Michael O. Hottiger
• Keywords: IRF3; IRF1

PARP7 was reported to promote tumor growth in a cell-autonomous manner and by repressing the antitumor immune response. Nevertheless, molecular mechanism of how PARP7-mediated ADP-ribosylation exerts these effects cancer cells remains elusive. Here, we identified as nuclear cysteine-specific mono-ADP-ribosyltransferase that modifies targets critical for regulating transcription, including AP-1 transcription factor FRA1. Loss FRA1 via inhibition RBN-2397 or mutation site C97 increased degradation proteasome PSMC3. The reduction protein levels promoted IRF1- IRF3-dependent cytokine well proapoptotic gene expression, culminating CASP8-mediated apoptosis. Furthermore, high expression indicative inhibitor response FRA1-positive lung breast cells. Collectively, our findings highlight connected roles emphasize clinical potential inhibitors FRA1-driven cancers.