Exploiting synthetic lethality in DNA repair for cancer therapy
Thomas Helleday
Gray Institute for Radiation Oncology and Biology, University of Oxford, UK
DNA repair and damage response pathways are activated as a tumour barrier at early stages during cancer development. Here, we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double strand breaks. A new concept for cancer therapy is to amplify endogenous tumour-specific DNA lesions, to specifically kill tumour cells.
Based on this concept we report that BRCA2 defective breast cancers can be specifically targeted using inhibitors of Poly(ADP-ribose) polymerase (PARP). We show that BRCA2 deficient cells, as a result of their recombination deficiency, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed forks are no longer repaired. We exploit this requirement to specifically kill BRCA2 deficient tumours by PARP inhibition alone.
When replication forks stall, a multifaceted response, including several DNA repair and cell cycle checkpoint pathways, is activated in order to ensure faithful DNA replication. Here, we show that PARP1 binds to and is activated by stalled replication forks. PARP1 collaborates with Mre11 to promote replication fork restart following release from replication blocks, most likely through Mre11-mediated resection of DNA. Both PARP1 and PARP2 are required for subsequent homologous recombination to promote cell survival following replication blocks. Our data suggest that PARP1 and PARP2 act as sensors of replication stress and are required for Mre11-mediated restart and recombination repair of stalled replication forks.
