PARG regulates the proteasomal degradation of TARG1

ADP-ribosylation (ADPr) is a reversible modification of macromolecules critical for the regulation of genome stability, stress responses, and proteostasis. While the roles of ADPr transferases such as PARP1/2 and TNKS1/2 are well established, the functions and regulatory mechanisms of ADPr hydrolases are still poorly understood. Here, we identify a function of the poly(ADP-ribose) glycohydrolase PARG in regulating protein degradation. Using quantitative proteomics, we show that PARG inhibition depletes protein levels of the mono-ADPr hydrolase TARG1. We demonstrate that this TARG1 depletion is both PAR and proteasome dependent and identify the E3 ubiquitin ligases HUWE1 and TRIP12 as mediators of this process. Our findings establish TARG1 as a substrate of PAR-dependent protein degradation and uncover a PARG-dependent mechanism controlling its stability. This work highlights an interplay between the two ADP-ribosyl hydrolases, with implications for the refinement of PARG-targeted therapeutic strategies.

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Publication Details

Journal
Cell Reports
Published
2026-01-01
DOI
https://doi.org/10.1016/j.celrep.2025.116789
Primary Topic
PARP inhibition in cancer therapy
Type
article
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article

PARG regulates the proteasomal degradation of TARG1

R Kurzbauer, Sara C. Buch-Larsen, Michael L. Nielsen, Thomas Agnew et al.
Cell Reports
PARP inhibition in cancer therapy
article

PARG regulates the proteasomal degradation of TARG1

R Kurzbauer, Sara C. Buch-Larsen, Michael L. Nielsen, Thomas Agnew, Michael Tellier, Roderick J. O’Sullivan, Joséphine Groslambert, Callum Henfrey, Ivo A. Hendriks, Evgeniia Prokhorova, Jonas D. Elsborg, Chatrin Chatrin, Tim Clausen, Ivan Ahel, Song My Hoang, Jonathan Barosso-Gonzalez
article en

Abstract

ADP-ribosylation (ADPr) is a reversible modification of macromolecules critical for the regulation of genome stability, stress responses, and proteostasis. While the roles of ADPr transferases such as PARP1/2 and TNKS1/2 are well established, the functions and regulatory mechanisms of ADPr hydrolases are still poorly understood. Here, we identify a function of the poly(ADP-ribose) glycohydrolase PARG in regulating protein degradation. Using quantitative proteomics, we show that PARG inhibition depletes protein levels of the mono-ADPr hydrolase TARG1. We demonstrate that this TARG1 depletion is both PAR and proteasome dependent and identify the E3 ubiquitin ligases HUWE1 and TRIP12 as mediators of this process. Our findings establish TARG1 as a substrate of PAR-dependent protein degradation and uncover a PARG-dependent mechanism controlling its stability. This work highlights an interplay between the two ADP-ribosyl hydrolases, with implications for the refinement of PARG-targeted therapeutic strategies.

Cell ReportsVol. 45(1)
University of Leicester (GB), Research Institute of Molecular Pathology (AT), Novo Nordisk Foundation (DK), University of Oxford (GB), UPMC Hillman Cancer Center (US)
Openalex Percentile: Top 96%
PARP inhibition in cancer therapy
DOIOpen Access PDFOpenAlex
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