Douglas K Bishop

Homologous recombination of DNA repairs DNA damage and also creates the physical connections between chromosomes needed for reductional chromosome segregation during meiosis. We study two recombination proteins, Dmc1 and Rad51 that are related to the bacterial repair protein, RecA. The mechanisms of recombinational repair of damage induced double strand breaks in DNA (DSBs) and the mechanism of meiotic recombination are very closely related in terms of the DNA intermediates that form; DSBs are normal intermediates in most or all meiotic recombination. There are, however critical differences in how meiotic recombination is regulated as compared to mitotic recombinational repair. Our research is directed at understanding how Dmc1's function is specialized for meiosis, how the functions of Rad51 and Dmc1 differ, how the two proteins interact with one another during meiosis, and how the two proteins interact with components of the synaptonemal complex. Our studies have shown that while the functions of Rad51 and Dmc1 overlap, they are also functionally distinct.

Using biochemical techniques we recently showed that, like yeast Rad51 protein, yeast Dmc1 protein promotes strand exchange. These results open the door to future efforts to reconstitute regulated homologous recombination reactions in vitro.

We were first to show that recombination proteins can be detected at multiple subnuclear sites during recombination using immunostaining techniques. We have used this method to identify proteins trequired for recruitment of recombinase to double strand break sites in mitotic and meiotic cells. Among such regulators is the breast cancer susceptibility gene BRCA1. We have shown that BRCA1 promotes recombinase assembly and we are currently working to determine the mechanism through which BRCA1 mediates this effect

Homologous recombination of DNA repairs DNA damage and also creates the physical connections between chromosomes needed for reductional chromosome segregation during meiosis. We study two recombination proteins, Dmc1 and Rad51 that are related to the bacterial repair protein, RecA. The mechanisms of recombinational repair of damage induced double strand breaks in DNA (DSBs) and the mechanism of meiotic recombination are very closely related in terms of the DNA intermediates that form; DSBs are normal intermediates in most or all meiotic recombination. There are, however critical differences in how meiotic recombination is regulated as compared to mitotic recombinational repair. Our research is directed at understanding how Dmc1's function is specialized for meiosis, how the functions of Rad51 and Dmc1 differ, how the two proteins interact with one another during meiosis, and how the two proteins interact with components of the synaptonemal complex. Our studies have shown that while the functions of Rad51 and Dmc1 overlap, they are also functionally distinct.

Using biochemical techniques we recently showed that, like yeast Rad51 protein, yeast Dmc1 protein promotes strand exchange. These results open the door to future efforts to reconstitute regulated homologous recombination reactions in vitro.

We were first to...

Sheridan, S.D., Yu, X., Roth, R., Heuser, J.E., Sehorn, M.G., Sung, P., Egelman, E.H., and Bishop, D.K. (2008). A comparative analysis of Dmc1 and Rad51 nucleoprotein filaments. Nucleic Acids Res 36, 4057-4066. 

McMahill, M. S., Sham, C. W., and Bishop, D. K. (2007) Synthesis Dependent Strand Annealing in Meiosis. PLoS Biology, 5: 2589-2601 

Martin, R., Orelli, B.J. , Yamazoe, M. , Minn A.J. , Takeda, S., and Bishop, D.K. (2007) RAD51 Up-regulation suppresses a BRCA1 null mutant and is a Feature of BRCA1-Deficient Breast Tumors. Cancer Res 67:9658-9665 

Holzen, T. Shah, P., Olivares, H. and Bishop D. K. (2006) Tid1 promotes dissociation of Dmc1 from non-recombinogenic sites on meiotic chromatin. Genes Dev 20: 2593-2604  

Chen, Y.-K., Leng, C.-H., Olivares, H., Lee, M.-H.,, Chang, Y.-C., Ti, S.-C.,Lo, Y.-H., Wang, A. H.-J., Chang, C.-S., Bishop, D.K., Hsueh, Y.-P., and Twang, T.-F.(2004) Heterodimeric Complexes of Hop2p and Mnd1p Function with Dmc1 to Promote Meiotic Homolog Juxtaposition and Strand-Assimilation. Proc. Natl. Acad. Sci. USA 101: 10572-10577. 

Bishop, D.K. and Zickler, D. (2004) Early Decision: Meiotic Crossover Interference prior to stable strand exchange and synapsis (Review) Cell 117, 117, 9-15. 

Connell, P. P., Siddiqui, N., Hoffman, S., Kuang, A., Khatipov, E.-A., Weichselbaum, R. R., and Bishop, D.K. (2004) A hotspot for RAD51C interactions revealed by a peptide that sensitizes cells to cisplatin. Cancer Research 64, 3002-3005 

Gasior, S. L., Olivares, H., Ear, U., Hari, D.M., Weichselbaum, R.R., and Bishop, D.K. (2001) Assembly of RecA-like recombinases: Distinct roles for mediator proteins in mitosis and meiosis. Proc. Natl. Acad. Sci. USA 98:8411-8418. 

Hong, E. L., Shinohara, A., and Bishop, D.K. (2001) S. cerevisiae Dmc1 protein promotes renaturation of ssDNA and assimilation of ssDNA into homologous super-coiled duplex DNA. J. Biol. Chem. 276:41906-41912. 

Bhattacharyya, A., Ear, U., Koller, B., Weichselbaum, R. and Bishop, D. K. (2000) The breast cancer-susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA crosslinking agent cisplatin. J. Biol. Chem. 60:2520-2526. 

Bishop, D.K. (1994) RecA homologues Dmc1 and Rad51 interact to form multiple nuclear complexes before meiotic chromosome synapsis. Cell 79:1081-1092.  

Sheridan, S.D., Yu, X., Roth, R., Heuser, J.E., Sehorn, M.G., Sung, P., Egelman, E.H., and Bishop, D.K. (2008). A comparative analysis of Dmc1 and Rad51 nucleoprotein filaments. Nucleic Acids Res 36, 4057-4066. 

McMahill, M. S., Sham, C. W., and Bishop, D. K. (2007) Synthesis Dependent Strand Annealing in Meiosis. PLoS Biology, 5: 2589-2601 

Martin, R., Orelli, B.J. , Yamazoe, M. , Minn A.J. , Takeda, S., and Bishop, D.K. (2007) RAD51 Up-regulation suppresses a BRCA1 null mutant and is a Feature of BRCA1-Deficient Breast Tumors. Cancer Res 67:9658-9665 

Holzen, T. Shah, P., Olivares, H. and Bishop D. K. (2006) Tid1 promotes dissociation of Dmc1 from non-recombinogenic sites on meiotic chromatin. Genes Dev 20: 2593-2604  

Chen, Y.-K., Leng, C.-H., Olivares, H., Lee, M.-H.,, Chang, Y.-C., Ti, S.-C.,Lo, Y.-H., Wang, A. H.-J., Chang, C.-S., Bishop, D.K., Hsueh, Y.-P., and Twang, T.-F.(2004) Heterodimeric Complexes of Hop2p and Mnd1p Function with Dmc1 to Promote Meiotic Homolog Juxtaposition and Strand-Assimilation. Proc. Natl. Acad. Sci. USA 101: 10572-10577.