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
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.
