Inhibition of poly(ADP-ribose) glycohydrolase (PARG) specifically kills BRCA2-deficient tumor cells.

Abstract	Poly(ADP-ribose) glycohydrolase (PARG), removes poly(ADP-ribose) subunits from proteins that have previously been modified by poly(ADP-ribose) polymerse. This ensures that modification is transient, and it is suggested that removal of poly(ADP-ribose) is essential for some types of DNA repair. Here we show increased γH2AX foci formation and increased homologous recombination when PARG is inhibited. These effects are reduced when replication is inhibited, suggesting that in the absence of PARG activity, replication forks collapse, and homologous recombination is induced for repair. Consistent with this, we show that cells deficient in the homologous recombination protein BRCA2 are sensitive to PARG depletion or inhibition. These data raise the exciting possibility that PARG inhibitors may be used to specifically kill BRCA2 and other homologous recombination-deficient tumors.
Authors	Catherine Fathers, Ross M Drayton, Svetlana Solovieva, Helen E Bryant
Journal	Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 11 Issue 5 Pg. 990-7 (Mar 01 2012) ISSN: 1551-4005 [Electronic] United States
PMID	22333589 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	BRCA2 Protein H2AX protein, human Histones Hydrolyzable Tannins Poly(ADP-ribose) Polymerase Inhibitors RNA, Small Interfering Poly Adenosine Diphosphate Ribose Poly(ADP-ribose) Polymerases Glycoside Hydrolases poly ADP-ribose glycohydrolase
Topics	Animals BRCA2 Protein (antagonists & inhibitors, genetics, metabolism) CHO Cells Cricetinae Cricetulus DNA Damage DNA Repair DNA Replication Glycoside Hydrolases (antagonists & inhibitors, genetics, metabolism) Histones (metabolism) Homologous Recombination (drug effects) Humans Hydrolyzable Tannins (pharmacology) MCF-7 Cells Poly Adenosine Diphosphate Ribose (metabolism) Poly(ADP-ribose) Polymerase Inhibitors Poly(ADP-ribose) Polymerases (metabolism) RNA Interference RNA, Small Interfering (metabolism)

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