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The is a human poly (ADP-ribose) glycohydrolase. It is an enzyme that will catalyze the hydrolysis of glycosides, here more specifically it will produce a free ADP-ribose. This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression on a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies.

Structure

Structural highlights

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This protein has four principal domains on a single peptide chain: a A-domain, a catalytic domain and two substrate binding domains[1].

The first 456 amino acids of the peptide chain form the A-domain. Then from 610 to 795 amino acids is located the catalytic domain. This catalytic domain can binding with other proteins with two amino acids (the 726 and 727 amino acids). Next the second substrate binding domain is located from the 869 th to the 874th amino acids. [2] So, most of the amino acids form the A-domain and the catzlytic domain and only few amino acids (8 a.a) make links with other proteins.

Secondary Structure

This protein is 37% and 13% . Indeed, it has 25 helices on 198 residues and 23 strands on 74 residues. It has also few 3/10 helices. [3] Involving the torsion angles the backbone and the sidechain have to be differentiated. Indeed none residue does't respect the Ramachandran's angle, whereas in sidechains where 2% of the residues are Ramachandran outliers because they have non-rotameric sidechains. [4]

Quaternary Structure

Poly(ADP-ribose)glycohydrolase interact with PCNA or NUDT5. When this protein is binding with NUDT5 it can remodeling chromatin.[5]

Function

The protein is a complex composed of the poly (ADP-ribose) glycohydrolase (PARG) and the anthraquinone PDD00013907. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free ligand (of identification number on PDB: 7JB) that can bind to the PARG creating the protein complex 6HMM.

Post-translational modifications and anthraquinone

There are several possible post-translational modifications to stabilize DNA. Most commonly they would be phosphorylation, acetylation or methylation ^[3]. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds ^[4]. This allows the repair of single-strand breaks on DNA ^[5]. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the poly (ADP-ribose) polymerase (PARP) to free itself from the damaged, now repaired, site and completes as such reparation ^[6].

The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies ^[6].

The mechanism

As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype PARP1, will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will then recruit other repair proteins to the site.

The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished^[5]. This degradation is important because without PARG the repair cycle cannot be completed ^[7] and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR ^[8].

Diseases and Relevance

Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damaging is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death^[5][6]. Consequently, the inhibition of PARG might be a solution how to destroy for example tumour cells.

For the opponent PAR protein there has already been a lot of research in this field but not for PARG. As there are no close homologues of PARG^[5], this protein provides a potential target in drug discovery.

As the protein in complex with the anthraquinone does not work properly anymore [6], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting like the 6HMM complex. For now the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell^[6].