title: Mre11-dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1.
abstract: PARP inhibitors are currently being used in clinical trials to treat BRCA1- or BRCA2-defective tumors, based on the synthetic lethal interaction between PARP1 and BRCA1/2-mediated homologous recombination (HR). However, the molecular mechanisms that drive this synthetic lethality remain unclear. Here, we show increased levels of Mre11, a key component of MRN (Mre11-Rad50-Nbs1) complex that plays a role in the restart of stalled replication forks and enhanced resection at stalled replication forks in BRCA2-deficient cells. BRCA2-deficient cells also showed hypersensitivity to the Mre11 inhibitor mirin. Interestingly, PARP1 activity was required to protect stalled forks from Mre11-dependent degradation. Resistance to PARP inhibition in BRCA2-mutant cells led to reduced levels of Mre11 foci and also rescued their sensitivity to mirin. Taken together, our findings not only show that Mre11 activity is required for the survival of BRCA2 mutant cells but also elucidate roles for both the BRCA2 and PARP1 proteins in protecting stalled replication forks, which offers insight into the molecular mechanisms of the synthetic lethality between BRCA2 and PARP1.
authors.affiliation: Gray Institute for Radiation Oncology & Biology, Department of Oncology, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Songmin
authors.initials: S
authors.lastname: Ying
authors.forename: Freddie C
authors.initials: FC
authors.lastname: Hamdy
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
mesh_terms: D024682:BRCA2 Protein / Q000502:physiology*; D049109:Cell Proliferation; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D000076228:MRE11 Homologue Protein; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D011744:Pyrimidinones / Q000494:pharmacology; D013871:Thiones / Q000494:pharmacology
chemical_list: C526365:6-(4-hydroxyphenyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011744:Pyrimidinones; D013871:Thiones; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000076228:MRE11 Homologue Protein