The interplay of TARG1 and PARG protects against genomic instability

Joséphine Groslambert; Evgeniia Prokhorova; Anne R. Wondisford; Callum Tromans-Coia; Celeste Giansanti; Jennifer Jansen; Gyula Timinszky; Matthias Dobbelstein; Dragana Ahel; Roderick J. O’Sullivan; Ivan Ahel

Cell Reports (Sep 2023)

The interplay of TARG1 and PARG protects against genomic instability

Joséphine Groslambert,
Evgeniia Prokhorova,
Anne R. Wondisford,
Callum Tromans-Coia,
Celeste Giansanti,
Jennifer Jansen,
Gyula Timinszky,
Matthias Dobbelstein,
Dragana Ahel,
Roderick J. O’Sullivan,
Ivan Ahel

Affiliations

Joséphine Groslambert: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
Evgeniia Prokhorova: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
Anne R. Wondisford: Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer, University of Pittsburgh, Pittsburgh, PA, USA
Callum Tromans-Coia: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
Celeste Giansanti: Department of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany
Jennifer Jansen: Department of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany
Gyula Timinszky: Laboratory of DNA Damage and Nuclear Dynamics, Institute of Genetics, Biological Research Centre, Eötvös Loránd Research Network (ELKH), 6276 Szeged, Hungary
Matthias Dobbelstein: Department of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany
Dragana Ahel: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
Roderick J. O’Sullivan: Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer, University of Pittsburgh, Pittsburgh, PA, USA
Ivan Ahel: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK; Corresponding author

Journal volume & issue: Vol. 42, no. 9
p. 113113

Abstract

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Summary: The timely removal of ADP-ribosylation is crucial for efficient DNA repair. However, much remains to be discovered about ADP-ribosylhydrolases. Here, we characterize the physiological role of TARG1, an ADP-ribosylhydrolase that removes aspartate/glutamate-linked ADP-ribosylation. We reveal its function in the DNA damage response and show that the loss of TARG1 sensitizes cells to inhibitors of topoisomerase II, ATR, and PARP. Furthermore, we find a PARP1-mediated synthetic lethal interaction between TARG1 and PARG, driven by the toxic accumulation of ADP-ribosylation, that induces replication stress and genomic instability. Finally, we show that histone PARylation factor 1 (HPF1) deficiency exacerbates the toxicity and genomic instability induced by excessive ADP-ribosylation, suggesting a close crosstalk between components of the serine- and aspartate/glutamate-linked ADP-ribosylation pathways. Altogether, our data identify TARG1 as a potential biomarker for the response of cancer cells to PARP and PARG inhibition and establish that the interplay of TARG1 and PARG protects cells against genomic instability.

CP: Molecular biology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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