The interplay of TARG1 and PARG protects against genomic instability

Groslambert, Josephine and Prokhorova, Evgeniia and Wondisford, Anne R. and Tromans-Coia, Callum and Giansanti, Celeste and Jansen, Jennifer and Timinszky, Gyula and Dobbelstein, Matthias and Ahel, Dragana and O'Sullivan, Roderick J. and Ahel, Ivan (2023) The interplay of TARG1 and PARG protects against genomic instability. CELL REPORTS, 42 (9). No-113113. ISSN 2211-1247

Preview

Text GroslambertJ.pdf Available under License Creative Commons Attribution. Download (3MB) | Preview

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-ri-bosylhydrolase 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.

Actions (login required)

Edit Item