Work

The interplay of TARG1 and PARG protects against genomic instability

Year: 2023

Type: article

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.

Source: Cell Reports

DOI: 10.1016/j.celrep.2023.113113

Authors: 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

Institutions: University of Oxford, University of Pittsburgh, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Universitätsmedizin Göttingen, University of Göttingen, HUN-REN Szegedi Biológiai Kutatóközpont, Institute of Genetics, Hungarian Research Network

Language: English

Topic: PARP inhibition in cancer therapy

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $5,460

Funders: University of Pittsburgh, Wellcome Trust, Ovarian Cancer Research Alliance, Cancer Research UK, Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences

Awards: G1454986793, G1888827638, G230613184, Serine ADP-ribosylation in genome stability and human disease, G2826741850, Reversible ADP-ribosylation signaling in the control of coronavirus infection, G3194705467, Serine ADP-ribosylation in genome stability and human disease, G5309921416, G5810331965, Protein poly(ADP-ribosyl)ation in genome stability and human disease., G741073515, Integrated biological and mathematical studies of TTP pathway dynamics, Inhibition of the ALT pathway by interfering with Poly-ADP-Ribose metabolism, Predoctoral Training in Pharmacological Sciences

OpenAlex ID: W4386493123

FWCI: 1.959

Cites: 69

Cited by: 19

Related to: 10