2. Academic Validation
  3. Ubiquitin pathway blockade reveals endogenous ADP-ribosylation marking PARP7 and AHR for degradation

Ubiquitin pathway blockade reveals endogenous ADP-ribosylation marking PARP7 and AHR for degradation

  • EMBO J. 2026 Jan;45(1):261-277. doi: 10.1038/s44318-025-00656-1.
Andrii Gorelik 1,  Nina Đukić 2,  Rebecca Smith 2,  Chatrin Chatrin 2,  Osamu Suyari 2,  Jason Matthews 3 4,  Ivan Ahel 5
Affiliations

Affiliations

  • 1 Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK. [email protected].
  • 2 Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK.
  • 3 Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, 0317, Oslo, Norway.
  • 4 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • 5 Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK. [email protected].
PMID: 41326691 DOI: 10.1038/s44318-025-00656-1
Abstract

ADP-ribosylation is an important protein post-translational modification catalysed by a family of PARP Enzymes in humans and is involved in DNA damage and immunity among Other processes. While poly-ADP-ribosylation has been established as a protein degradation signal in several cases, the role of mono-ADP-ribosylation in protein turnover has remained elusive and mostly relies on overexpression systems. Here, we describe a way to visualise high levels of endogenous ADP-ribosylation by inhibiting the ubiquitin pathway. By blocking ubiquitylation/Proteasome, we found that ADP-ribosylation by at least three different PARPs (PARP7, PARP1 and TNKS) can be greatly induced. We discovered that specific activation of the Aryl Hydrocarbon Receptor (AHR) pathway in combination with the ubiquitin pathway inhibition promotes quantitative ADP-ribosylation of PARP7 targets, including the mono-ADP-ribosyltransferase PARP7 itself and AHR. We found that DTX2 is the E3 Ligase responsible for degrading ADP-ribosylated PARP7, AHR and Other PARP7 substrates. This PARP7-DTX2 crosstalk establishes a mechanism to rapidly shut down AHR-mediated transcription by decreasing its protein levels. Taken together, our findings uncover a paradigm where mono-ADP-ribosylation acts as a degradation MARK.

Keywords

ADP-Ribose; Aryl Hydrocarbon Receptor; PARP7; Protein Degradation; Ubiquitin.

Figures
Products