Show simple item record

dc.contributor.authorGravells, P
dc.contributor.authorGrant, E
dc.contributor.authorSmith, Kate M
dc.contributor.authorJames, Dominic I
dc.contributor.authorBryant, H
dc.date.accessioned2017-04-03T10:06:13Z
dc.date.available2017-04-03T10:06:13Z
dc.date.issued2017-04
dc.identifier.citationSpecific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase. 2017, 52:81-91 DNA Repairen
dc.identifier.issn1568-7856
dc.identifier.pmid28254358
dc.identifier.doi10.1016/j.dnarep.2017.02.010
dc.identifier.urihttp://hdl.handle.net/10541/620235
dc.description.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.
dc.language.isoenen
dc.rightsArchived with thanks to DNA repairen
dc.titleSpecific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase.en
dc.typeArticleen
dc.contributor.departmentAcademic Unit of Molecular Oncology, Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Beech Hill Road, Sheffield, S10 2RXen
dc.identifier.journalDNA Repairen
refterms.dateFOA2018-12-17T14:53:43Z
html.description.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.


Files in this item

Thumbnail
Name:
1-s2.0-S1568786416303627-main.pdf
Size:
2.246Mb
Format:
PDF
Description:
Full text, Open Access Article

This item appears in the following Collection(s)

Show simple item record