Douglas Bishop, PhD
Mechanisms of Meiotic Recombination and Recombinational Repair of DNA Damage

Professor, Department of Radiation and Cellular Oncology, Committee on Cancer Biology, Committee on Genetics, Genomics & Systems Biology, Molecular Genetics and Cell Biology

Amherst College, Amherst, MA, B.S. Biology,1980
Harvard University, Cambridge, MA, Ph.D., Biology, 1988

 

Research Summary

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 required 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.

More detailed information on current projects in the lab may be found at our lab web site's Research Projects page.


Selected Publications

Cloud, V., Chan, Y.-L., Grubb, J., Budke, B., and Bishop D. K. (2012) Rad51 Is an Accessory Factor for Dmc1-Mediated Joint Molecule Formation During Meiosis. Science 337, 1222-1225. (PubMed)

Danilowicz, C., Feinstein, E., Conover, A., Coljee, V.W., Vlassakis, J., Chan, Y.-L., Bishop, D.K., and Prentiss, M. (2011) RecA homology search is promoted by mechanical stress along the scanned duplex DNA. Nucleic Acids Res. 40, 1717-1727. (PubMed)

Shah PP, Zheng X, Epshtein A, Carey JN, Bishop DK, Klein HL. (2010) Swi2/Snf2-related translocases prevent accumulation of toxic Rad51 complexes during mitotic growth. Mol Cell.39(6):862-72. (PubMed)

Ferrari, S., Grubb, J., and Bishop, D. (2009) The Mei5-Sae3 complex mediates Dmc1 activity in Saccharomyces cerevisiae. J Biol Chem 284 18,11766-11770. (PubMed)

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. (PubMed)

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

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. (PubMed)

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. (PubMed)

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. (PubMed)

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

 

 
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