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DNA Repair (Amst). 2017 Apr;52:81-91. doi: 10.1016/j.dnarep.2017.02.010. Epub 2017 Feb 17.

Specific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase.

Author information

1
Academic Unit of Molecular Oncology, Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
2
Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, United Kingdom.
3
Academic Unit of Molecular Oncology, Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, United Kingdom. Electronic address: h.bryant@sheffield.ac.uk.

Abstract

Poly(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.

KEYWORDS:

BARD1; BRCA1; Breast cancer; FAM175A (ABRAXAS); PALB2; PARG inhibition; Synthetic lethality

PMID:
28254358
PMCID:
PMC5360195
DOI:
10.1016/j.dnarep.2017.02.010
[Indexed for MEDLINE]
Free PMC Article

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