PARG

Official Full Name

poly(ADP-ribose) glycohydrolase

Organism

Homo sapiens

GeneID

8505

Background

Poly(ADP-ribose) glycohydrolase (PARG) is the major enzyme responsible for the catabolism of poly(ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

Synonyms

PARG99;

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Detailed Information

PARG in cancer treatment

Poly (ADP-ribosyl)ation has some involvements in cellular processes of DNA repair, transcription, cell division, cell death and so on, since its role in post-translational modification. Rapid production of poly (ADR-ribose) (PAR) at DNA breaks gives rise to local chromatin relaxation and recruitment of repair factors with a strong affinity for PAR. So, in some ways, the amount of PAR produced may be the reflector of the severity of the DNA insult, also a contributor to the cell decision to initiate either survival or death programmes. With localization to different cellular compartments of its multiple isoforms, the PAR degrading enzyme poly (ADP-ribose) glycobydrolase (PARG) is encoded by a single gene. PARG isoforms depletion is embryonically lethal in mice, and hypomorphic mutant mice are sensitive to ionizing radiation and alkylating agents. Expression of all PARG inhibited by shRNA in cells has demonstrated that presence of PARG is a necessity for efficient repair of single and double strand breaks and oxidized bases. In the live-cell microscopy and laser microirradiation conducted experiment, it was shown that all PARG isoforms except for the mitochondrial localized one can be efficiently recruited to DNA damage sites. PARG recruitment at sites of DNA damage is contributed by the binding to PCNA, which was identified to be the work of functional PCNA-binding motif within the PARG sequence. At least two pathways are related to this recruitment, one is PAR-dependent and the other is PCNA-dependent.

Radiotherapy and chemotherapy have been regarded as powerful but nonselective methods for killing cancer cells, however, in recent years, cancer therapy has been revolutionized by precision medicine, which is based on the concept of selective targeting of cancer cells. Poly (ADP-ribose) glycohydrolase (PARG) can exploit replication deficiencies of cancer cells to make complementation for PARP inhibitors, which has a broad range of cancer types with different sources of genomic instability to be targeted. In clinics, PARP inhibitors used in cancer therapy were demonstrated to be in combination with other drugs, like PARG inhibitors, for the purpose of overcoming resistance.

Figure 1. Schematic diagram showing the effect of dePARylation inhibitors on DDR. (Muzaffer Ahmad Kassab, et al. 2020)

References:

Kassab M A, Yu L L, Yu X. Targeting dePARylation for cancer therapy. Cell & Bioscience, 2020, 10(1): 1-9.
Slade D. PARP and PARG inhibitors in cancer treatment. Genes & development, 2020, 34(5-6): 360-394.
Mortusewicz O, Fouquerel E, Ame J C, et al. PARG is recruited to DNA damage sites through poly (ADP-ribose)-and PCNA-dependent mechanisms. Nucleic acids research, 2011, 39(12): 5045-5056.

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