PARG regulates the proteosomal degradation of TARG1

ADP-ribosylation (ADPr) is a reversible modification of macromolecules critical for the regulation of genome stability, stress responses, and proteostasis. While the roles of ADPr transferases such as PARP1/2 and TNKS1/2 are well established, the cellular functions and regulatory mechanisms of ADPr hydrolases are still poorly understood. Here, we identify a previously uncharacterized function of the poly(ADP-ribose) glycohydrolase PARG in maintaining protein stability. Using quantitative proteomics, we show that PARG inhibition perturbs proteome homeostasis and leads to the depletion of the mono-ADPr hydrolase TARG1 at the protein—but not transcript—level. We demonstrate that this loss results from enhanced proteasomal degradation and reveal that TARG1 downregulation is PAR- and proteasome-dependent, with the E3 ubiquitin ligase HUWE1 identified as a central mediator of this process. Our findings establish TARG1 as a physiological substrate of PAR-dependent protein degradation and uncover a PARG-dependent mechanism for regulating TARG1 stability. This work highlights a new dimension of interplay between the two ADP-ribosyl hydrolases, with direct implications for the design and refinement of PARG-targeted therapeutic strategies.