Molecular mechanisms of mitotic DNA synthesis in BRCA2-deficient cells
Primary Supervisor: Professor Madalena Tarsounas
Aberrant replication causes cells lacking BRCA2 to enter mitosis with under-replicated DNA, which activates a repair mechanism known as mitotic DNA synthesis (MiDAS). We have recently mapped genome-wide the sites where mitotic DNA synthesis (MiDAS) occurs in BRCA1/2-deficient cells (Groelly et al, Molecular Cell 2022), using state-of-the-art technologies (e.g. MiDAS-seq, high-content microscopy) and found that they co-localise with sites of R-loop formation. We now aim to investigate the roles of ATR/ATM kinases, as well as of MUS81 (Lai et al. Nat. Communications 2017) and other nucleases in regulating this process. Overall, this project combines cell/molecular biology and microscopy approaches with high-throughput technologies and bioinformatics to understand how BRCA1 and BRCA2 facilitate DNA replication and how this, in turn, impacts chromosome segregation during mitosis
- cell/molecular biology;
- high-content microscopy;
- high-throughput sequencing technologies;
- Groelly FJ, Fawkes M, Dagg RA, Blackford AN and Tarsounas M. 2022. Targeting DNA damage response pathways in cancer. Nature Reviews Cancer in press.
- Groelly FJ, Dagg RA, Petropoulos M, Rosetti G, Panagopoulos A, Paulsen T, Karamichali A, Jones SE, Ochs F, Dionellis VS, Puig-Lombardi E, Miossec MJ, Lockstone H, Legube G, Blackford AN, Altmeyer M, Halazonetis TD and Tarsounas M. 2022. Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells. Molecular Cell 82: 3382-3397.