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.
Highlights
Inherited mutations in either the BRCA1 or BRCA2 genes, involved in homologous recombination (HR), predispose to an increased risk for breast and ovarian cancer
Because it has been established that PARP can mediate recruitment of Mre11 to replication forks [7, 13], we wanted to test whether the number of Mre11 foci is higher in BRCA2-defective cells
Such a heightened degree of resection can be explained by a novel function for BRCA2 in protecting stalled replication forks from being processed by Mre11, a function that has recently been shown to be distinct from the role of BRCA2 in HR [9]
Summary
Inherited mutations in either the BRCA1 or BRCA2 genes, involved in homologous recombination (HR), predispose to an increased risk for breast and ovarian cancer. We and others have shown that cells and tumors mutated in these genes are hypersensitive to inhibitors of PARP [1, 2]. Such PARP inhibitors are currently being evaluated in clinical trials for cancers with BRCA mutations [3]. This hypersensitivity to PARP inhibitors has been explained by a synthetic lethal interaction between BRCA and PARP. The molecular mechanism to explain this synthetic lethality was suggested to be accumulation of DNA single-strand breaks (SSB) in PARPinhibited cells that produce substrates for HR at collapsed replication forks.
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