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PARG regulates the proteosomal degradation of TARG1

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Jonas D. Elsborg

LAB HEAD: Michael L. Nielsen

PROVIDER: PXD065407 | Pride | 2026-01-02

REPOSITORIES: Pride

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	20211210_EXPL0_LC12_SCL-IAH_PR_U-C-C_01_F1.raw	Raw
	20211210_EXPL0_LC12_SCL-IAH_PR_U-C-C_01_F2.raw	Raw
	20211210_EXPL0_LC12_SCL-IAH_PR_U-C-C_01_F3.raw	Raw
	20211210_EXPL0_LC12_SCL-IAH_PR_U-C-C_01_F4.raw	Raw
	20211210_EXPL0_LC12_SCL-IAH_PR_U-C-C_01_F5.raw	Raw

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 PARG regulates the proteasomal degradation of TARG1

Project description:ADP-ribosylation 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 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 regulating protein degradation. Using quantitative proteomics, we show that PARG inhibition depletes protein levels of the mono-ADPr hydrolase TARG1. We demonstrate that this TARG1 depletion is both PAR- and proteasome-dependent, and identify the E3 ubiquitin ligases HUWE1 and TRIP12 as mediators of this process. Our findings establish TARG1 as a substrate of PAR-dependent protein degradation and uncover a PARG-dependent mechanism controlling its stability. This work highlights a new dimension of interplay between the two ADP-ribosyl hydrolases, with implications for the refinement of PARG-targeted therapeutic strategies.

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Project description:ADP-ribosylation (ADPr) signaling plays a crucial role in the DNA damage response. Inhibitors against the main enzyme catalyzing ADPr after DNA damage – PARP1 – are used as targeted therapies against breast cancers with BRCA1/2 mutations. However, development of resistance to PARP inhibitors (PARPi) is a major obstacle in treating patients. To better understand the role of ADPr in PARPi sensitivity, we used Liquid Chromatography-Mass Spectrometry (LC-MS) for systems level analysis of the ADP-ribosylome in six breast cancer cell lines with different PARPi sensitivities. We identified 1632 sites on 777 proteins, primarily on serine residues, with a high site overlap of DNA damage-related proteins across all cell lines, demonstrating high conservation in ADPr signaling after DNA damage. We furthermore observed site-specific differences in ADPr intensities in PARPi-sensitive BRCA mutants, and unique ADPr sites in PARPi-resistant BRCA mutant cells, which we notably show to have low PARG levels and longer PARP1 ADPr chains.

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Project description:ARH3/ADPRHL2 and PARG are the major enzymes reversing ADP-ribosylation in vertebrates, yet their functions in vivo remain unclear. ARH3 is the only hydrolase able to removes serine-linked mono(ADP-ribose) (MAR), but is much less efficient than PARG against poly(ADP-ribose) (PAR) chains in vitro. Here, by utilizing ARH3-deficient cells, we demonstrate that endogenous MARylation persists on chromatin throughout the cell cycle including mitosis, and is, surprisingly, well tolerated. Conversely, persistent PARylation is highly toxic and has distinct physiological effects, in particular on active transcription histone marks such as H3K9ac and H3K27ac. Furthermore, we reveal a synthetic lethal interaction between ARH3 and PARG, and identify loss of ARH3 as a mechanism of PARP inhibitor resistance, both of which can be exploited in cancer therapy. Finally, we extend our findings to neurodegeneration, suggesting that patients with inherited ARH3 deficiency suffer from stress-induced pathogenic increase in PARylation that can be mitigated by PARP inhibition.

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