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  3. CRISPR screens and quantitative proteomics reveal remodeling of the aryl hydrocarbon receptor-driven proteome through PARP7 activity

CRISPR screens and quantitative proteomics reveal remodeling of the aryl hydrocarbon receptor-driven proteome through PARP7 activity

  • Proc Natl Acad Sci U S A. 2025 Jun 17;122(24):e2424985122. doi: 10.1073/pnas.2424985122.
Andrii Gorelik 1 2,  Joao A Paulo 2,  Christina B Schroeter 2 3,  Melanie Lad 4,  Abigail Shurr 4,  Chara Mastrokalou 4,  Samrah Siddiqi 1,  Osamu Suyari 1,  John Brognard 5,  David Walter 4,  Jason Matthews 6 7,  Timothy M Palmer 8,  Steven P Gygi 2,  Ivan Ahel 1
Affiliations

Affiliations

  • 1 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
  • 2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
  • 3 Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf 40225, Germany.
  • 4 Cancer Research Horizons, Joint AstraZeneca-Cancer Research Horizons Functional Genomics Centre, Cambridge CB2 0AW, United Kingdom.
  • 5 Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702.
  • 6 Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo 0317, Norway.
  • 7 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 8 Biomedical Institute for Multimorbidity, Centre for Biomedicine, Hull York Medical School, University of Hull, Hull HU6 7RX, United Kingdom.
PMID: 40493189 DOI: 10.1073/pnas.2424985122
Abstract

PARP7 is an enzyme that uses donor substrate NAD+ to attach a single ADP-ribose moiety onto proteins related to immunity, transcription, and cell growth and motility. Despite the importance of PARP7 in these processes, PARP7 signaling networks remain underresearched. Here, we used genome-wide CRISPR screens and multiplex quantitative proteomics in distinct lung Cancer cell lines treated with a PARP7 Inhibitor to better understand PARP7 molecular functions. We find that manipulating the Aryl Hydrocarbon Receptor (AHR) transcriptional activity mediates PARP7 Inhibitor sensitivity and triggers robust changes to the AHR-controlled proteome (AHR-ome). One of the striking features of such AHR-ome remodeling was the downregulation of filamins A and B concurrent with the induction of the corresponding E3 ubiquitin Ligase ASB2. We also show that suppressor of cytokine signaling 3 (SOCS3) crosstalks to AHR. Inhibition of PARP7 in SOCS3 knockout cells leads to reduced viability compared to wild-type cells treated with a PARP7 Inhibitor. Our results reveal signaling interplay between PARP7, AHR, and SOCS3 and establish an invaluable resource to study the role of PARP7 in the regulation of AHR signaling and innate immunity through its ADP-ribosyl transferase activity.

Keywords

ADP-ribosylation; CRISPR; PARP; aryl hydrocarbon receptor; proteomics.

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