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PARG: a new target for therapies against cancer?

Poly (ADP-Ribose) Glycohydrolase Regulates Retinoic Acid Receptor-Mediated Gene Expression.

Le May N, Iltis I, Amé JC, Zhovmer A, Biard D, Egly JM, Schreiber V, Coin F.

Mol Cell Dec. 14, 2012


Oct. 25, 2012

Following today’s interest in new treatments against cancer currently in test, French researchers from the Institut de génétique et de biologie moléculaire et cellulaire (IGBMC) and from the Institut de recherche de l’école de biotechnologie de Strasbourg (Irebs) have just brought to light the role of a new molecule in gene transactivation by retinoic acid, widening therapeutic perspectives for this molecular target. These results are published on 25th October in Molecular Cell.

What is Poly(ADP-ribosyl)ation?

Poly(ADP-ribosyl)ation is a mechanism launched in response to genotoxic agents affecting genetic information. Some poly(ADP-ribose) polymerases (PARP), and more particularly PARP-1, detect DNA lesions and catalyze the synthesis of poly(ADP-ribose) that binds to proteins, initializing the repair of the lesion. PARP inhibitors are currently on trial as therapeutic adjuvants in order to better raise cancer cell sensitivity towards some chemotherapeutic agents. Poly(ADP-ribosyl)ation mechanism is reversible and tightly regulated by Poly(ADP-ribose) glycohydrolase (PARG), the role of which is to suppress ADP-riboses from proteins. In conclusion, PARP-1 and PARG seems to form a team of molecules dedicated to the maintenance of genome integrity. PARG is still poorly studied but, according to its close relationships with PARP, researchers now try to decipher the complexity of its functions.

 

IGBMC/Irebs: a productive collaboration

Valérie Schreiber’s team at the Irebs is focused on the respective roles of PARP and PARG in genome integrity and tumor development. On the other hand, the group of Frédéric Coin at the IGBMC is specialized in the study of gene expression. As it has already been proven that PARP-1 was implicated in gene transactivation by retinoic acid, the two teams have worked together to study the potential role of its close partner, PARG, in this process. This collaboration has been profitable and researchers finally demonstrated that PARG was both implicated in the modulation of transcriptional activity and genome repair. They notably revealed the antagonistic roles of PARP-1 and PARG on a histone demethylase involved in chromatin remodeling, an essential step for gene expression under the control of retinoic acid.

 

This is the first study to show the mechanism of PARG activity in the regulation of gene expression, promoting this molecule, like PARP-1, as a new promising therapeutic target for cancer treatment.

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