DNA Repair and Cancer
Research in a Nutshell
DNA repair deficiency results in increased cancer susceptibility, while DNA repair in cancer cells reduces effectiveness of cancer chemotherapeutics. Melanoma cells have elevated levels of some DNA repair proteins. We are investigating their involvement in the extreme resistance shown by melanoma to conventional chemotherapy and have developed a DNA repair inhibitor as a candidate novel therapy. We have also identified a novel DNA damage response mechanism. Rather than increasing levels of key homologous recombination protein RAD51 on encountering DNA crosslinks during replication, melanoma cells shut down RAD51 synthesis and instead boost levels of a translesion synthesis DNA polymerase to allow replication to proceed. This unusual response may be a more appropriate strategy for an aggressive and rapidly growing tumour that enables it to better survive chemotherapy. Around 50% of serous ovarian cancers have defective homologous recombination repair and are most likely to be initially sensitive to platinum therapy. The rest are homologous recombination proficient and show most resistance to current available therapies. We are investigating the hypothesis that cancers in this group can be rendered chemotherapy sensitive by treatment with specific DNA damage response, or cell cycle checkpoint inhibitors.
- Professor Charlie Gourley, University of Edinburgh
Melanoma, ovarian cancer, DNA repair, DNA damage response, cell cycle checkpoints, cancer therapy
Mammalian cell culture, GM mice, DNA damage and repair assays