2. Academic Validation
  3. The interplay of TARG1 and PARG protects against genomic instability

The interplay of TARG1 and PARG protects against genomic instability

  • Cell Rep. 2023 Sep 6;42(9):113113. doi: 10.1016/j.celrep.2023.113113.
Joséphine Groslambert 1,  Evgeniia Prokhorova 1,  Anne R Wondisford 2,  Callum Tromans-Coia 1,  Celeste Giansanti 3,  Jennifer Jansen 3,  Gyula Timinszky 4,  Matthias Dobbelstein 3,  Dragana Ahel 1,  Roderick J O'Sullivan 2,  Ivan Ahel 5
Affiliations

Affiliations

  • 1 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
  • 2 Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer, University of Pittsburgh, Pittsburgh, PA, USA.
  • 3 Department of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
  • 4 Laboratory of DNA Damage and Nuclear Dynamics, Institute of Genetics, Biological Research Centre, Eötvös Loránd Research Network (ELKH), 6276 Szeged, Hungary.
  • 5 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK. Electronic address: ivan.ahel@path.ox.ac.uk.
PMID: 37676774 DOI: 10.1016/j.celrep.2023.113113
Abstract

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.

Keywords

ADP-ribosylation; CP: Molecular biology; DNA damage; PARG inhibitor; PARP inhibitor; TARG1; cancer.

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  • HY-132167
    99.79%, PARP Inhibitor