title: 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.affiliation: The Institute for Cancer Studies, Department of Oncology, Faculty of Medicine Dentistry and Health Sciences, University of Sheffield, Sheffield, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fathers
authors.forename: Ross M
authors.initials: RM
authors.lastname: Drayton
authors.forename: Svetlana
authors.initials: S
authors.lastname: Solovieva
authors.forename: Helen E
authors.initials: HE
authors.lastname: Bryant
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D059765:Homologous Recombination / Q000187:drug effects; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology; D061986:MCF-7 Cells; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D024682:BRCA2 Protein; C468783:H2AX protein, human; D006657:Histones; D047348:Hydrolyzable Tannins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase