Specific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase.
AffiliationAcademic Unit of Molecular Oncology, Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX
MetadataShow full item record
AbstractPoly(ADP-ribosylation) of proteins following DNA damage is well studied and the use of poly(ADP-ribose) polymerase (PARP) inhibitors as therapeutic agents is an exciting prospect for the treatment of many cancers. Poly(ADP-ribose) glycohydrolase (PARG) has endo- and exoglycosidase activities which can cleave glycosidic bonds, rapidly reversing the action of PARP enzymes. Like addition of poly(ADP-ribose) (PAR) by PARP, removal of PAR by PARG is also thought to be required for repair of DNA strand breaks and for continued replication at perturbed forks. Here we use siRNA to show a synthetic lethal relationship between PARG and BRCA1, BRCA2, PALB2, FAM175A (ABRAXAS) and BARD1. In addition, we demonstrate that MCF7 cells depleted of these proteins are sensitive to Gallotannin and a novel and specific PARG inhibitor PDD00017273. We confirm that PARG inhibition increases endogenous DNA damage, stalls replication forks and increases homologous recombination, and propose that it is the lack of homologous recombination (HR) proteins at PARG inhibitor-induced stalled replication forks that induces cell death. Interestingly not all genes that are synthetically lethal with PARP result in sensitivity to PARG inhibitors, suggesting that although there is overlap, the functions of PARP and PARG may not be completely identical. These data together add further evidence to the possibility that single treatment therapy with PARG inhibitors could be used for treatment of certain HR deficient tumours and provide insight into the relationship between PARP, PARG and the processes of DNA repair.
CitationSpecific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase. 2017, 52:81-91 DNA Repair
- Inhibition of poly(ADP-ribose) glycohydrolase (PARG) specifically kills BRCA2-deficient tumor cells.
- Authors: Fathers C, Drayton RM, Solovieva S, Bryant HE
- Issue date: 2012 Mar 1
- Poly(ADP-Ribose) Glycohydrolase (PARG) vs. Poly(ADP-Ribose) Polymerase (PARP) - Function in Genome Maintenance and Relevance of Inhibitors for Anti-cancer Therapy.
- Authors: Harrision D, Gravells P, Thompson R, Bryant HE
- Issue date: 2020
- Targeting poly(ADP-ribose) glycohydrolase to draw apoptosis codes in cancer.
- Authors: Tanuma SI, Shibui Y, Oyama T, Uchiumi F, Abe H
- Issue date: 2019 Sep
- Poly(ADP-ribose) glycohydrolase mediates oxidative and excitotoxic neuronal death.
- Authors: Ying W, Sevigny MB, Chen Y, Swanson RA
- Issue date: 2001 Oct 9
- Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality.
- Authors: Gogola E, Duarte AA, de Ruiter JR, Wiegant WW, Schmid JA, de Bruijn R, James DI, Guerrero Llobet S, Vis DJ, Annunziato S, van den Broek B, Barazas M, Kersbergen A, van de Ven M, Tarsounas M, Ogilvie DJ, van Vugt M, Wessels LFA, Bartkova J, Gromova I, Andújar-Sánchez M, Bartek J, Lopes M, van Attikum H, Borst P, Jonkers J, Rottenberg S
- Issue date: 2018 Jun 11