The interplay of TARG1 and PARG protects against genomic instability
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723011245 |
| _version_ | 1827823088999333888 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Joséphine Groslambert |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T02:06:28Z |
| format | Article |
| id | doaj.art-b876a752cfb24b1990b0c4df1c0ffbba |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T02:06:28Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-b876a752cfb24b1990b0c4df1c0ffbba2023-09-07T04:43:50ZengElsevierCell Reports2211-12472023-09-01429113113The interplay of TARG1 and PARG protects against genomic instabilityJoséphine Groslambert0Evgeniia Prokhorova1Anne R. Wondisford2Callum Tromans-Coia3Celeste Giansanti4Jennifer Jansen5Gyula Timinszky6Matthias Dobbelstein7Dragana Ahel8Roderick J. O’Sullivan9Ivan Ahel10Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UKSir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UKDepartment of Pharmacology and Chemical Biology, UPMC Hillman Cancer, University of Pittsburgh, Pittsburgh, PA, USASir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UKDepartment of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, GermanyDepartment of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, GermanyLaboratory of DNA Damage and Nuclear Dynamics, Institute of Genetics, Biological Research Centre, Eötvös Loránd Research Network (ELKH), 6276 Szeged, HungaryDepartment of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, GermanySir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UKDepartment of Pharmacology and Chemical Biology, UPMC Hillman Cancer, University of Pittsburgh, Pittsburgh, PA, USASir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723011245CP: Molecular biology |
| spellingShingle | 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 The interplay of TARG1 and PARG protects against genomic instability Cell Reports CP: Molecular biology |
| title | The interplay of TARG1 and PARG protects against genomic instability |
| title_full | The interplay of TARG1 and PARG protects against genomic instability |
| title_fullStr | The interplay of TARG1 and PARG protects against genomic instability |
| title_full_unstemmed | The interplay of TARG1 and PARG protects against genomic instability |
| title_short | The interplay of TARG1 and PARG protects against genomic instability |
| title_sort | interplay of targ1 and parg protects against genomic instability |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723011245 |
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