Homologous recombination at stalled replication forks
Many cytotoxic cancer therapies exploit the high proliferation rates of cancer cells by specifically interfering with DNA replication, thus generating lethal DNA damage. Inhibiting DNA replication fork progression leads to fork stalling, which can cause accumulation of DNA double-strand breaks (DSBs). These processes activate homologous recombination repair.
Our recent data suggest that the recombination factor RAD51 is recruited to stalled replication forks, where it promotes fork restart, but also potentially detrimental processes that increase the likelihood of DSB formation. This project will further investigate the exact roles of recombination factors at stalled replication forks. This will help to better understand how replication inhibitor therapies work in recombination-defective cancers.
This self-funded PhD project combines our expertise in labelling of nascent DNA with nucleoside analogues (DNA fibre method) to study mammalian replication fork progression with standard cell and molecular biology techniques to investigate the role of homologous recombination factors at stalled replication forks.
1. Jones RM, Kotsantis P, Stewart GS, Groth P, Petermann E (2014) BRCA2 and RAD51 promote double-strand break formation and cell death in response to Gemcitabine. Mol Cancer Ther 13: 2412-2421
2. Jones RM, Petermann E (2012) Replication fork dynamics and the DNA damage response. Biochem J 443: 13-26
3. Petermann E, Orta ML, Issaeva N, Schultz N, Helleday T (2010) Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51- mediated pathways for restart and repair. Mol Cell 37: 492-502