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Updated: Sep 16, 2025

Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells
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The IFN I response in tumor cells is shaped by PARP7-p300/CBP interactions through distinct loss- and

Ivan Rodriguez Siordia, Sonja Rieth, Rory Morgan

    Biorxiv : the Preprint Server for Biology
    |July 9, 2025
    PubMed

    Insights

    Poly (ADP-ribose) polymerase 7 (PARP7) regulates type I interferon (IFN-β) by modifying co-activators p300 and CBP. PARP7 inhibitors induce IFN-β via a dual mechanism involving both loss-of-function and gain-of-function effects.

    Area of Science:

    • Oncology
    • Immunology
    • Molecular Biology

    Background:

    • Poly (ADP-ribose) polymerase 7 (PARP7) is a mono-ADP-ribosyl (MAR) transferase that suppresses type I interferon (IFN-β) in tumor cells.
    • PARP7 is a validated drug target, and its inhibitors increase IFN-β expression, but the precise mechanism remains unclear due to unknown substrates.

    Purpose of the Study:

    • To identify nuclear substrates of PARP7 and elucidate the mechanism by which PARP7 inhibitors regulate IFN-β expression.

    Main Methods:

    • Utilized an optimized analog-sensitive chemical genetic (ASCG) approach to identify PARP7 substrates.
    • Investigated the interaction between PARP7, p300, and CBP using biochemical and cellular assays.
    • Assessed the impact of disrupting PARP7-p300/CBP interaction on IFN-β expression in colorectal cancer cells.

    Main Results:

    • Identified co-activators p300 and CBP as nuclear PARP7 substrates.
    • Discovered an α-helical domain in PARP7 crucial for p300/CBP interaction, MARylation, and proteasome degradation.
    • Demonstrated that disrupting PARP7-p300/CBP interaction inhibits PARP7's suppression of IFN-β.
    • Observed that PARP7 inhibitors induce IFN-β more effectively than PARP7 knockout in a p300/CBP-dependent manner.

    Conclusions:

    • PARP7 regulates IFN-β by MARylating p300/CBP, and this interaction is essential for suppressing IFN-β in cancer cells.
    • PARP7 inhibitors induce IFN-β through a dual mechanism: inhibiting p300/CBP MARylation (loss-of-function) and stabilizing the PARP7-p300/CBP complex (gain-of-function).
    • These findings provide novel insights into the mechanism of PARP7 inhibitors and their potential in cancer immunotherapy.

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