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Newly Identified Enzyme Could Rival PARPs as a Drug Target

By Sharon Kingman
Staff Writer

LONDON – Study of a family affected by an inherited neurological disease has helped to reveal the identity of an enzyme that could point the way to new therapies for cancer and cardiovascular disease.

The existence of the enzyme, which plays a role in maintaining cell survival and DNA repair, has been predicted for at least 30 years and has even been shown to operate in cell cultures. But, until it was linked with the gene defect in the family studied, no one knew what it was.

Now an international team of scientists have pinpointed it and confirmed what it does. The researchers said they hope the enzyme could become an important target for new drugs aimed at inhibiting growth of cancer cells.

Ivan Ahel, group leader at the Paterson Institute for Cancer Research at the University of Manchester in the UK, told BioWorld International: "The question is, can we intentionally inhibit this protein and others that operate in the same pathway? We can only speculate at this stage that this protein could be another target similar to that targeted by the class of anticancer drugs known as PARP inhibitors."

Work already has begun, he said, on finding small-molecule inhibitors of the protein. "It has been suggested that such inhibitors could perhaps be beneficial in cancer treatment or potentially in acute cardiovascular conditions, but we don't have any proof of that yet," he added.

An account of the study is published in the March 12, 2013, issue of EMBO Journal in a paper, titled "Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease." The first author is Reza Sharifi.

Ahel has been working for some years on the cellular processes that enable the repair of damaged DNA. Some proteins that assist with DNA repair need chemical tags added to regulate their activity in a timely fashion. One type of chemical tag important for cell regulation is made of chains of adenosine diphosphate (ADP) coupled to a sugar, ribose.

The family of proteins that catalyze that process of ADP-ribosylation is known as the poly(ADP-ribose) (PAR) polymerases – also called PARPs. The drugs known as PARP inhibitors target those enzymes, preventing them from adding the PAR chains.

From the research reported in EMBO Journal, however, it seems that removal of the PAR chains from proteins is also essential for normal cell function.

Scientists knew that the enzyme PAR glycohydrolase (PARG) could remove most of the PAR chains – but it does not remove the very first ADP-ribose unit attached to the protein. It was known that such an enzyme existed, because researchers could detect its activity in mammalian cell cultures.

The additional clue to its identity came when Ahel and his collaborators, who include Scott Williams, of the National Institutes of Health, and Gyula Timinszky and Andreas Ladurner, both of Ludwig Maximilians University in Munich, combined their research efforts with Sharifi's work at the Human Genetics Research Center at St George's University of London.

Sharifi's group had been studying a family affected by an inherited neurodegenerative disease. The researchers had identified a mutation in a gene called c6orf130, which was present only in affected members of the family, and not in unaffected members or in more than 1,200 chromosomes from control subjects. No one knew, however, what the function of the protein encoded by c6orf130 was.

Ahel's group, in collaboration with John Denu at the University of Wisconsin, had shown previously that the C6orf130 protein could remove the ADP-ribose group from a chemical compound called acetyl-ADP-ribose. Writing in the EMBO Journal article, the authors said: "Given the similarity of the chemical bond between the glutamate and ADP-ribose in mono(ADP-ribosyl)ated proteins and the bond in the acetylated ADP-ribose, we postulated that C6orf130 could function as a long-sought protein that reverses the protein mono(ADP-ribosyl)ation synthesised by PARPs."

The experiments they carried out showed that was indeed the case. Because of the role of C6orf130 in removing the ADP-ribose unit attached to the protein, they suggested renaming it terminal ADP-Ribose protein glycohydrolase, or TARG1.

Ahel and his colleagues predict that TARG1 might not be the only protein with that function. "Our next steps will involve looking at other proteins that belong to the same pathway," he said. "We will also search for proteins that act downstream of TARG1, to unravel new cellular processes controlled by protein ADP-ribosylation."