In meiosis, chromosomes replicate once, then undergo two rounds of segregation to generate haploid meiotic products. The aberrant segregation of chromosome during meiosis generates products that are aneuploid have an incorrect number of chromosomes). In humans, meiotic aneuploidy is the leading cause of pregnancy loss, congenital birth defects, and mental retardation. Exposure to environmental agents (pollutants, pesticides hormone mimetics, etc.) is implicated as a risk factor. However, it is difficult to gauge significant effects in humans and there are no good models for large-scale screening. The goal of our work is to develop and validate a system for high-through put screening (HTS) of chemical libraries to identify those that cause meiotic aneuploidy (meiotic aneugenes). The system is based on the unique biology of the fission yeast Schizosaccharomyces pombe, in which meiosis can be induced in a synchronous fashion and in which meiotic chromosome mis-segregation can be monitored directly. Selectable markers will be configured to allow quantitative analysis of the frequency of meiotic aneuploidy following exposure to chemical agents. Additional features will be incorporated into the system for secondary screening and to permit identification of specific molecular mechanisms by which any given chemical affects meiosis. The system will be validated and calibrated by using mutants that affect meiotic sister chromatid cohesion and meiotic recombination and by testing chemicals known to cause meiotic errors. Upon validation, the systems will be made available to a molecular libraries screening center network site for HTS screening of potential meiotic aneugens.
Gao J, Davidson MK, and Wahls WP. (2009) Phosphorylation-independent regulation of Atf1-promoted meiotic recombination by stress-activated, p38 kinase Spc1 of fission yeast. PLoS One 4(5):e5533.
Wahls WP, Siegel ER, and Davidson MK. (2008) Meiotic recombination hotspots of fission yeast are directed to loci that express non-coding RNA. PLoS One 3(8):e2887.
Gao J, Davidson MK, and Wahls WP. (2008) Distinct regions of ATF/CREB proteins Atf1 and Pcr1 control recombination hotspot ade6-M26 and the osmotic stress response. Nucleic Acids Res 36(9):2838-51.
Wahls, W.P., K.M. DeWall, and M.K. Davidson (2005) Mapping of ssDNA nicks within dsDNA genomes by two-dimensional gel electrophoresis. J. Ark. Acad. Sci. 59:178-186.
DeWall, K.M., M.K. Davidson, W.D. Sharif, C.A. Wiley, and W.P. Wahls (2005) A DNA binding motif of meiotic recombinase Rec12 (Spo11) defined by essential glycine-202; and persistence of Rec12 protein after completion of recombination. Gene, 356, 77-84
Davidson, M.K., H.K. Shandilya, K. Hirota, K. Ohta, and W.P. Wahls (2004) Atf1-Pcr1-M26 complex directly links stress-activated MAPK and PKA pathways via chromatin remodeling of cgs2+. J. Biol. Chem. 279, 50857-50863.
Davidson, M.K., N.P. Young, G.G. Glick, and W.P. Wahls (2004) Meiotic chromosome segregation mutants identified by insertional mutagenesis of Schizosaccharomyces pombe; tandem-repeat, single-site integrations. Nucleic Acids Res., 32, 4400-4410.
Wu, H., J. Gao, W.D. Sharif, M.K. Davidson, and W.P. Wahls (2004). Purification, folding, and characterization of Rec12 (Spo11) meiotic recombinase of fission yeast. Protein Expr. Purif. 38, 136-144.
Sharif, W.D., M.K. Davidson, and W.P. Wahls (2003) Rec12 (Spo11) recombinase of fission yeast promotes a backup, distributive pathway for chromosome segregation in meiosis I. J. Ark. Acad. Sci. 57, 147-155.
Davidson, M.K., H.K. Shandilya, W.D. Sharif, and W.P. Wahls (2003) Atf1oPcr1oM26 complex and nucleosome remodeling promote double-strand DNA break-induced meiotic recombination. Rec. Res. Dev. Mol. Cell. Biol. 4, 189-208. [invited review / book chapter]
Sharif, W.D., G.G. Glick, M.K. Davidson, and W.P. Wahls. (2002) Distinct functions of S. pombe Rec12 (Spo11) protein and Rec12-dependent crossover recombination (chiasmata) in meiosis I; and a requirement for Rec12 in meiosis II. Cell Chromo. 1, 1-14.
Davidson MK, Russ PK, Glick GG, Hoffman LH, Chang, MS, and FR Haselton. (2000) Reduced expression of the adherens junction protein cadherin-5 in a diabetic retina. Am J Ophthalmol 129: 267-269.
Lecanda F, Cheng SL, Shin CS, Davidson MK, Warlow P, Avioli LV, Civitelli R. (2000) Differential regulation of cadherins by dexamethasone in human osteoblastic cells. J Cell Biochem 77(3): 499-506.
Russ PK, Davidson MK, Hoffman LH, and FR Haselton. (1998) Partial characterization of the human retinal endothelial cell tight and adherens junction complexes. Invest Ophth Vis Sci 39: 2203.
Xu Y, Guo D-F, Davidson MK, Inagami T, and G Carpenter. (1997) Interaction of the adaptor protein shc with the adhesion molecule cadherin. J Biol Chem 272(21): 13463-13466.