biostudies-literatureGroslambert JCancer Research UKUniversity of PittsburghNational Cancer InstituteNCI NIH HHSNational Institutes of HealthWellcome TrustOvarian Cancer Research AllianceNIGMS NIH HHSNemzeti Kutatási Fejlesztési és Innovációs Hivatal113113https://www.ebi.ac.uk/biostudies/studies/S-EPMC10933786biostudies-literatureUnknown42(9)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.Cell reportsThe interplay of TARG1 and PARG protects against genomic instability.PMC10933786R01CA207209220107T32 GM133332813369R01262316210634/Z/18/ZC35050/A2228422310732GM133332P30 CA047904K143248R01 CA20720922284101794210634S_4211Jansen JO'Sullivan RJAhel ITiminszky GProkhorova EAhel DDobbelstein MGroslambert JTromans-Coia CGiansanti CWondisford ARfalseThe interplay of TARG1 and PARG protects against genomic instability.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.2023-01-01T00:00:00Z2023 Sep2026-06-29T03:16:31.083Z2025-04-06T14:31:57.683ZS-EPMC109337863767677410.1016/j.celrep.2023.113113