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

Abstract

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

PARP14 mediated SQSTM1/p62 cysteine ADP-ribosylation is counteracted by the SARS-CoV-2 macrodomain

“…The remaining modifications are in intrinsically disordered regions near the ZZ-type zinc finger (ZZ domain) and the nuclear localization/export sequence (NLS/NES). These p62-specific cysteine residues were also identified in the NSCLC cell line NCI-H1975 58 under unstimulated conditions, supporting that these cells are in a viral mimicry primed state 59 .…”

“…1B) in A549 cells due to p62's well-described functions in viral clearance 56,57 . In addition, a modification at C331 was identified in NCI-H1975 58 , which is located in the LC3 interaction region (LIR). The remaining modifications are in intrinsically disordered regions near the ZZ-type zinc finger (ZZ domain) and the nuclear localization/export sequence (NLS/NES).…”

“…Our peptide enrichment strategy and mass spectrometry workflow, previously detailed in another publication 84 , were consistently applied in the experiments conducted for this manuscript.…”

Distinct Capabilities in NAD Metabolism Mediate Resistance to NAMPT Inhibition in Glioblastoma

“…These results may in part be explained by the decrease in the expression of PARPBP and TIPARP in FK866-treated cells. These proteins have previously been associated with resistance to DNA damage and apoptosis, respectively [ 47 , 48 ]. Whilst we did not observe any significant changes in apoptosis with FK866 alone, others have shown that when NAMPT inhibitors are combined with TMZ, the ROS/JNK signalling pathway is activated, leading to significant increases in apoptosis in vitro [ 49 ].…”