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bioRxiv · 10.1101/2025.06.30.662483

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.·Rieth, S.·Jeltema, D.·Morgan, R.·Tullis, J.·Orth, J.·Yan, N.·Marx, A.·Cohen, M. S.
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Abstract

PARP7, a mono-ADP-ribosyl (MAR) transferase, is a key suppressor of the type I interferon (IFN-I) IFN{beta} 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 IFN-{beta} 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 -helical domain in PARP7 essential for p300/CBP interaction, MARylation, and proteasome degradation. Disrupting PARP7-p300/CBP interaction prevents PARP7s suppression of IFN{beta} in colorectal cancer cells. p300/CBP reciprocally regulate PARP7s activity and nuclear localization. Intriguingly, treatment with PARP7 inhibitors increased IFN{beta} expression more than PARP7 knockout in a p300/CBP-dependent manner. Our findings suggest that in some contexts, IFN{beta} 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). TeaserChemical genetics discovery of p300 and CBP as substrates of PARP7 that are essential for PARP7-mediated regulation of IFN{beta} via a dual mechanism.

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Siordia, I. R., Rieth, S., Jeltema, D., Morgan, R., Tullis, J., Orth, J., Yan, N., Marx, A., Cohen, M. S.. 2025-07-04. The IFN I response in tumor cells is shaped by PARP7-p300/CBP interactions through distinct loss- and gain-of-function mechanisms. https://doi.org/10.1101/2025.06.30.662483

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