Specific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase
| Autor: | Polly Gravells, Emma Grant, Helen E. Bryant, Dominic I. James, Kate M. Smith |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
DNA Replication
0301 basic medicine Synthetic lethality DNA Repair Glycoside Hydrolases DNA damage DNA repair Ubiquitin-Protein Ligases Poly ADP ribose polymerase Biology Biochemistry Article 03 medical and health sciences chemistry.chemical_compound Breast cancer Humans BARD1 Homologous Recombination Molecular Biology Poly(ADP-ribose) glycohydrolase PARG inhibition BRCA2 Protein PARG Manchester Cancer Research Centre BRCA1 Protein Tumor Suppressor Proteins ResearchInstitutes_Networks_Beacons/mcrc DNA replication Nuclear Proteins DNA Cell Biology BRCA1 Molecular biology Hydrolyzable Tannins 030104 developmental biology chemistry PALB2 Female Carrier Proteins Fanconi Anemia Complementation Group N Protein Homologous recombination FAM175A (ABRAXAS) DNA Damage |
| Zdroj: | Gravells, P, Grant, E, Smith, K M, James, D I & Bryant, H E 2017, ' Specific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase ', DNA Repair, vol. 52, pp. 81-91 . https://doi.org/10.1016/j.dnarep.2017.02.010 DNA Repair |
| DOI: | 10.1016/j.dnarep.2017.02.010 |
| Popis: | Highlights • A synthetic lethal screen for Poly(ADP-ribose)glycohydrolase (PARG) is presented. • SiRNA and the PARG inhibitors Gallotannin and PDD00017273 are used. • PARG is synthetically lethal with BRCA1, BRCA2, PALB2, FAM175A (ABRAXAS) and BARD1. • PARG inhibition induces DNA damage, stalled replication forks and homologous recombination. • The data support the validity of PARG as a target for therapy. 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. |
| Databáze: | OpenAIRE |
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