Biochemistry of Meiotic Recombination
Analysis of the structural architecture of meiotic recombination complexes
Characterization of the mechanism of homolog bias in meiosis
Role of Rad51 in genome stability and cancer
Small molecule stimulators of Rad51-DNA binding
Our colleague Dr. Philip Connell identified small molecules than enhance the ability of Rad51 to bind DNA. One of these molecules, called RS-1, was shown to stimulate recombination in a biochemical system and to enhance the resistance of cells to cisplatin, a DNA damaging agent used for cancer treatment (Jayathilaka et al. 2008). We seek to develop RS-1 and related compounds to improve the efficiency of CRISPR/Cas9-mediated genome editing. At the same time, we have showed RS-1 can also enhance the genotoxic activity of Rad51 by promoting its binding to undamaged DNA. This toxic activity of RS-1 can be used to target tumor cells because many tumors express abnormally high levels of Rad51 relative to healthy tissues. We recently provided proof-in-principle for this approach using a mouse tumor xenograft model; RS-1 slowed tumor growth in nude mice (Mason et al. 2013).
Tumor xenograft experiment. Tumors were established by introduction of PC3 human tumor cells into the hind limb of athymic nude mice. Following tumor establishment, mice were treated by peritoneal administration of RS-1 and tumor volumes measured 3 times a week thereafter (from Mason et al. 2013).
Jayathilaka, K., Sheridan, S.D., Bold, T.D., Bochenska, K., Logan, H.L., Weichselbaum, R.R., Bishop, D.K., and Connell, P.P. (2008). A Chemical compound that Stimulates the human Homologous Recombination protein RAD51. Proc Natl Acad Sci U S A 105, 15848-15853
Mason, J. M., Logan, H.L., Budke, B., Wu, M., Pawlowski, M., Kozikowski,A.P., Bishop, D.K., and Connell,, P.P. (2013) The RAD51-Stimulatory Compound RS-1 can Exploit the RAD51 Overexpression that Exists in Cancer Cells And Tumors. Cancer Res. 74:3546-355