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July 4th, 2025
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Oregon Health and Science University
cancer biology
biorxiv

The IFN I response in tumor cells is shaped by PARP7-p300/CBP interactions through distinct loss- and gain-of-function mechanisms

Siordia, I. R.Open in Google Scholar•Rieth, S.Open in Google Scholar•Jeltema, D.Open in Google Scholar•Morgan, R.Open in Google Scholar•Tullis, J.Open in Google Scholar•Orth, J.Open in Google Scholar•Yan, N.Open in Google Scholar•Marx, A.Open in Google Scholar•Cohen, M. S.Open in Google Scholar

PARP7, a mono-ADP-ribosyl (MAR) transferase, is a key suppressor of the type I interferon (IFN-I) IFNb in various tumor cells and a validated drug target. This negative regulation is reversed by small-molecule inhibitors of PARP7 catalytic activity, resulting in increased IFNb expression. Yet, the mechanism of action of PARP7 inhibitors remains unclear because the relevant substrates of PARP7-mediated MARylation are unknown. Using an optimized analog-sensitive chemical genetic (ASCG) approach, we identified the co-activators, p300 and CBP, as nuclear PARP7 substrates. We identified an alpha-helical domain in PARP7 essential for p300/CBP interaction, MARylation, and proteasome degradation. Disrupting PARP7-p300/CBP interaction prevents PARP7-mediated suppression of IFNb in colorectal cancer cells. p300/CBP reciprocally regulate PARP7 activity and nuclear localization. Intriguingly, treatment with PARP7 inhibitors increased IFNb expression more than PARP7 knockout in a p300/CBP-dependent manner. Our findings suggest that in some contexts, IFNb induction by PARP7 inhibitors occurs via two mechanisms: inhibiting MARylation of p300/CBP (loss-of-function) and stabilizing the PARP7-p300/CBP complex (gain-of-function).

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