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

Role of Rad51 in genome stability and cancer

Rad51 plays key roles in promoting DNA replication and in repairing DNA double strand breaks that form spontaneously or by the action of DNA damaging agents. We study the mechanisms through which Rad51 promotes DNA repair in human tumor cells. Recently we focused on a hitherto unappreciated function of Rad51. While Rad51 is best known for its role in promoting genome stability through DNA repair, our studies in budding yeast and human cells provided evidence that Rad51 (and its meiotic counterpart Dmc1) also promote genome instability. We further found that DNA translocases of the Rad54 family act to counter this genotoxic activity (Holzen et al. 2006, Shah et al. 2010, Mason et al. 2015). When the translocases are depleted, DNA replication and chromosome segregation are impaired. We are working to determine if and how the genome destabilizing activity of Rad51 contributes to tumor progression. We also seek to exploit the genotoxic activity of Rad51 to target tumor cells during cancer treatment (see project entitled “Small molecule stimulators of Rad51-DNA binding”).

Two partially separated HT1080 human tumor cell nuclei. The cell line was engineered to express very high levels of RAD51 and subject to depletion of DNA translocases RAD54L and RAD54B. Rad51 is in green. Note that in this situation, long filaments of RAD51 form. The results suggest that these filaments are bound to undamaged double stranded DNA (Mason). Note the DNA bridge between the two cells is decorated with RAD51. DAPI is a DNA-specific dye.

Holzen, T. M., Shah, P. P., Olivares, H. A., and Bishop, D. K. (2006) Tid1/Rdh54 Promotes Dissociation of Dmc1 from Non-Recombinogenic Sites on Meiotic Chromatin. Genes Dev. 20, 2593-2604

Shah, P.P., Zheng, X., Epshtein, A., Carey, J.N., Bishop, D.K., and Klein, H.L. (2010) Swi2/Snf2-Related Translocases Prevent Accumulation of Toxic Rad51 Complexes During Mitotic Growth. Mol. Cell 39, 862-872.

Mason, J.M., Dusad, K., Wright, W.D., Grubb, J., Budke, B., Heyer, W.-D., Connell, P.P., Weichselbaum, R.R., and Bishop, D.K. (2015) RAD54 family translocases counter genotoxic effects of RAD51 in human tumor cells. Nucleic Acids Res. doi: 10.1093/nar/gkv175

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