# Poly(ADP-ribose) glycohydrolase
**Poly(ADP-ribose) glycohydrolase (PARG)** is an enzyme that hydrolyzes the ribose-ribose bonds of poly([ADP-ribose](https://www.edgepedia.org/adp-ribose)) (PAR), a post-translational modification assembled on target proteins by poly(ADP-ribose) polymerases (PARPs) during [DNA repair](https://www.edgepedia.org/dna-repair) and other stress responses. Together with the PARP family, PARG regulates cellular PAR levels and is central to DNA maintenance and repair, and it has emerged as a drug target in cancer therapy.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC12123320/)
| Key fact | Detail |
|---|---|
| Reaction | Hydrolytic cleavage of the ribose-ribose bonds within PAR chains, releasing free PAR chains and mono(ADP-ribose) as the main product[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4030884/) |
| Position in PAR metabolism | The primary hydrolase degrading PAR, encoded by a single gene, whereas PAR synthesis is mediated by several PARP genes[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4030884/) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7485115/) |
| Catalytic mode | Both endo- and exo-glycohydrolase activity, preferentially exo, binding the two most distal ADP-ribose residues of a PAR chain[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7485115/) |
| Catalytic signature | A macrodomain catalytic loop with the sequence GGG(X₆)₈QEE, indispensable for activity and absent from other macrodomains[4](https://www.nature.com/articles/nrm3601.pdf) |
| Cancer link | PARG expression is elevated in many cancers, including breast, liver, prostate, and esophageal cancers, and is associated with unfavorable outcomes[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC12123320/) |
| Drug development | Several selective inhibitors exist (PDD00017273, COH34, JA2-4, JA2131); none has received clinical approval, though phase I trials of IDE161 and ETX-19477 are under way[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7485115/) • [5](https://academic.oup.com/narcancer/article/7/4/zcaf040/8313449) |
## Role in PAR metabolism
ADP-ribosylation is a reversible post-translational modification in which PARP enzymes cleave NAD+ and transfer ADP-ribose units onto acceptor proteins, building mono(ADP-ribose) or branched PAR chains. PARG is the principal enzyme that dismantles these chains. It possesses both endo-glycohydrolase and exo-glycohydrolase activity and preferentially performs the latter, binding the two most distal ADP-ribose residues of a chain; the two modes release free PAR chains and mono(ADP-ribose), respectively.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7485115/) The free mono(ADP-ribose) is further metabolized to AMP and ribose 5′-phosphate by NUDIX-family pyrophosphohydrolases.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7485115/)
PARG degrades most of the PAR polymer but leaves a single ADP-ribose attached to the acceptor protein.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC4522361/) Neither PARG nor the related hydrolase ARH3 can cleave the ester bond between the proximal ADP-ribose unit and the acceptor amino acid, so removal of that terminal linkage requires other enzymes.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4030884/) In PAR degradation PARG is 1 to 2 orders of magnitude more active than ARH3, the other PAR-degrading hydrolase.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC11488344/)
## Structure and catalysis
The catalytic domain of human PARG (residues 448 to 976) consists of a macrodomain flanked by N-terminal and C-terminal helical bundles.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC4522361/) Crystal structures of five PARG homologs, including human PARG (PDB 4AOD) and mouse PARG (4FC2), established how the enzyme recognizes PAR: the terminal ADP-ribose binds in a macrodomain pocket, positioning the ribose-ribose bond between the terminal and penultimate ADP-ribose units in hydrogen-bonding contact with the two glutamates of the PARG signature sequence.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4030884/) The catalytic loop carries the sequence GGG(X₆)₈QEE, which is indispensable for activity and distinguishes PARG from other macrodomain proteins.[4](https://www.nature.com/articles/nrm3601.pdf) A tyrosine clasp and an arginine switch around the active site contribute to substrate and inhibitor binding.[8](https://pubmed.ncbi.nlm.nih.gov/31827085/)
## Function in DNA repair and cancer
PARP1 builds PAR at DNA damage sites to recruit repair factors such as [XRCC1](https://www.edgepedia.org/xrcc1) in single-strand break repair, and PARG regulates the subsequent dissociation of these factors; PARP1 and PARG together also preserve replication fork integrity under replication stress.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC7050487/) Loss or inhibition of PARG, like loss of PARP, sensitizes cells to DNA-damaging agents, consistent with a role in timely DNA repair.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7485115/)
**Cancer relevance.** PARG expression is upregulated in many tumors; analysis of TCGA data found higher PARG expression in tumors than in matched normal tissue in all tumor types examined except kidney malignancies.[8](https://pubmed.ncbi.nlm.nih.gov/31827085/) Elevated PARG has been reported in breast, liver, prostate, and esophageal cancers and linked to unfavorable outcomes.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC12123320/) Inhibiting PARG causes PAR to accumulate on chromatin and traps PARP-DNA complexes, stalling repair, and can sensitize cells to radiation-induced DNA damage and suppress replication fork progression.[5](https://academic.oup.com/narcancer/article/7/4/zcaf040/8313449) • [8](https://pubmed.ncbi.nlm.nih.gov/31827085/)
## PARG inhibitors
Development of PARG inhibitors lagged behind that of PARP inhibitors. Early compounds included the natural polyphenol gallotannin and rhodanine-based inhibitors; newer cell-permeable inhibitors fall into three chemical classes, quinazolinedione-type (PDD00017273), naphthalene-type (COH34), and thioxanthine/methylxanthine derivatives (JA2-4 and JA2131), all of which compete with PAR for the PARG active site.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7485115/) A 1.7 Å crystal structure of human PARG bound to JA2-4 showed the inhibitor occupying the adenine-binding pocket, with the 6′-thiocarbonyl group of the JA2131 series increasing potency more than 50-fold over the corresponding carbonyl compound; JA2-4 inhibits PARG with an IC₅₀ of 0.9 μM.[8](https://pubmed.ncbi.nlm.nih.gov/31827085/)
**Therapeutic rationale.** Preclinical studies indicate that PARG inhibitors amplify and exploit replication-associated defects, offering a therapeutic window distinct from that of PARP inhibitors, which act through synthetic lethality with homologous recombination deficiencies.[10](https://www.sciencedirect.com/science/article/pii/S156878642500059X) • [9](https://pmc.ncbi.nlm.nih.gov/articles/PMC7050487/) PARG inhibition has also shown activity in [PARP inhibitor](https://www.edgepedia.org/parp-inhibitor)-resistant cells: in PARP inhibitor-resistant A172 glioblastoma cells, the methylxanthine inhibitor JA2131 showed killing comparable to [nedaplatin](https://www.edgepedia.org/nedaplatin).[8](https://pubmed.ncbi.nlm.nih.gov/31827085/) Combining PARG inhibition with PARP inhibition is being explored as a way to expand the therapeutic window, since on-target anemia leads to dose reductions or drug holidays in about half of PARP inhibitor patients.[11](https://www.aacr.org/wp-content/uploads/2026/04/AACR2026_Proceedings_Part-1.pdf)
## Clinical status
No PARG inhibitor has received clinical approval.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC12123320/) Clinical translation has begun, however: the PARG inhibitor IDE161 showed selective cytotoxicity toward DNA damage response-defective cancer cells while sparing normal cells in vitro, and ETX-19477 from 858 Therapeutics is in a phase I trial (NCT06395519).[5](https://academic.oup.com/narcancer/article/7/4/zcaf040/8313449) By contrast, four PARP inhibitors (olaparib, rucaparib, niraparib, and talazoparib) are clinically approved for breast, ovarian, pancreatic, and prostate cancers, a gap that reflects the later start of PARG drug development.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC12123320/) • [12](https://journals.sagepub.com/doi/10.1177/1078155219895066)
## References
1. [Prospects for PARG inhibitors in cancer therapy, Journal of Molecular Cell Biology](https://pmc.ncbi.nlm.nih.gov/articles/PMC12123320/)
2. [Molecular Insights into Poly(ADP-ribose) Recognition and Processing, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4030884/)
3. [PARG vs. PARP: Function in Genome Maintenance and Relevance of Inhibitors for Anti-cancer Therapy, Frontiers in Molecular Biosciences / PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7485115/)
4. [Macrodomain-containing proteins: regulating new intracellular functions of mono(ADP-ribosyl)ation, Nature Reviews Molecular Cell Biology](https://www.nature.com/articles/nrm3601.pdf)
5. [Targeting DNA repair mechanisms in cancer therapy, NAR Cancer](https://academic.oup.com/narcancer/article/7/4/zcaf040/8313449)
6. [The Rise and Fall of Poly(ADP-ribose). An Enzymatic Perspective, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4522361/)
7. [ADP-ribose hydrolases: biological functions and potential therapeutic targets, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC11488344/)
8. [Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death, Nature Communications (2019)](https://pubmed.ncbi.nlm.nih.gov/31827085/)
9. [PARP and PARG inhibitors in cancer treatment, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7050487/)
10. [PARPs and ADP-ribosyl hydrolases in cancer therapy: From drug targets to biomarkers, DNA Repair](https://www.sciencedirect.com/science/article/pii/S156878642500059X)
11. [Expanding the therapeutic window of PARP inhibitors by co-administering PARG inhibitors, AACR 2026 Proceedings](https://www.aacr.org/wp-content/uploads/2026/04/AACR2026_Proceedings_Part-1.pdf)
12. [PARP-inhibitor potpourri: A comparative review of class safety, efficacy, and cost, Journal of Oncology Pharmacy Practice](https://journals.sagepub.com/doi/10.1177/1078155219895066)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Enzyme classes and activities › Ubiquitination and protein-modification enzymes › Kinase, phosphatase, and ADP-ribosylation writer/eraser enzymes › ADP-ribosylation erasers and readers as enzymes*
*Initially written Sep 17, 2026 · Reviewed: Sep 30, 2026; Oct 21, 2026 · Edited: Oct 11, 2026; Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license