Research:

A predominant line of research in the Byers lab concerns the integration of mitotic spindle behavior with other aspects of the yeast cell cycle. Mutations that alter the formation and regulation of spindle pole body — the organelle that plays a key role as the nucleation center for spindle microtubule assembly — lead to identifiable changes in subcellular structure. Detailed analysis of these changes by immunocytochemical and electron microscope methods reveal phenotypic characteristics that provide a framework for isolating yet other mutations affecting important components of the cell cycle mechanism. Functions of current interest include those that mediate the formation of a new spindle pole body at the beginning of the cell cycle or control separation of the newly formed spindle pole from the parental one so that the spindle can form. Other genes under study serve to maintain integrity of the mitotic spindle during the anaphase movements. Key methods include cloning of the relevant genes, sequencing and deletion analysis, and creation of immunological tools (such as epitope-tagged alleles) for cytological studies.

Other research in the lab focuses on the mechanisms that mediate synapsis and recombination between homologous yeast chromosomes in prophase of meiosis. The protein encoded by the HOP1 (for homologue pairing) gene has been found to play a crucial role in assembly of the synaptonemal complex, an organelle that is highly conserved among eukaryotes. Other genes of interest coordinate the complex array of meiotic functions, some of them acting as “checkpoints’ to ensure appropriate rates of progression through successive stages of the overall process.

Selected Publications:

McDonald HB and Breck Byers. 1997. A proteasome cap subunit required for spindle pole body duplication in yeast. J Cell Biol 137:539-553.

Kironmai KM, Muniyappa K, Friedman DB, Hollingsworth NM, and Breck Byers. 1998. DNA-binding activities of Hop1 protein, a synaptonemal complex component of Saccharomyces cerevisiae. Mol Cell Biol 18:1424-1435.

Dirick L, Goetsch L, Ammerer G, and Breck Byers. 1998. Regulation of meiotic S phase by Ime2 and a Clb5,6-associated kinase in Saccharomyces cerevisiae. Science 281:1854-1857.

Mathias N,  Johnson S,  Breck Byers,  Goebl M.  Mar. 1999.  The abundance of cell cycle regulatory protein Cdc4p is controlled by interactions between its f box and Skp1p.  Mol.Cell Biol.   19(3):1759-67

Munoz-Centeno MC,  McBratney S,  Monterrosa A,  Breck Byers,  Mann C,  Winey M.  July 1999.  Saccharomyces cerevisiae MPS2 encodes a membrane protein localized at the spindle pole body and the nuclear envelope.  Mol Biol Cell. 10(7):2393-406.

Muniyappa, K., S. Anuradha, and Breck Byers. 2000. Yeast meiosis-specific protein Hop1 binds to G4 DNA and promotes its formation. Mol. Cell. Biol. 20: 1361-1369.

Comai, L., A.P. Tyagi, K. Winter, R. Holmes-Davis, S.H. Reynolds, Y. Stevens, and B. Byers. 2000. Phenotypic instability and rapid gene silencing in newly formed Arabidopsis allotetraploids. The Plant Cell. 12: 1551-1567.

Zheng, C.-J., S.-W. Guo, and B. Byers. 2000. Modeling the maternal-age dependency of reproductive failure and genetic fitness. Evolution and Development. 2: 203-207

additional publication listings available via PubMed

Research:

Walt Fangman retired at the end of 2004. The laboratory continues the research under Bonita J. Brewer.

Selected Publications:

Raghuraman, M.K., Winzeler, E.A., Collingwood, D., Hunt, S., Wodicka, L., Conway, A., Lockhart, D.J., Davis, R.W., Brewer, B.J., Fangman, W.L.. Replication dynamics of the yeast genome. Science. 294: 115-121, 05 Oct 2001

van Brabant A.J., Buchanan C.D., Charboneau E., Fangman W.L., Brewer B.J. An origin-deficient yeast artificial chromosome triggers a cell cycle checkpoint. Molecular Cell. 7(4): 705-13, Apr 2001

Ward T.R., Hoang M.L., Prusty R., Lau C.K., Keil R.L., Fangman W.L., Brewer B.J. Ribosomal DNA replication fork barrier and HOT1 recombination hot spot: shared sequences but independent activities. Molecular and Cellular Biology. 20(13): 4948-57, Jul 2000

van Brabant A.J., Fangman W.L., Brewer B.J. Active role of a human genomic insert in replication of a yeast artificial chromosome.. Mol Cell Biol. 19(6): 4231-40, Jun 1999

Donaldson A.D., Raghuraman M.K., Friedman K.L., Cross F.R., Brewer B. J., Fangman W. L. CLB5-dependent activation of late replication origins in S. cerevisiae.. Mol Cell. 2(2): 173-82, Aug 1998

additional publication listings available via PubMed

Research

One of the main questions addressed in Dr. Furlong’s laboratory is the genetic variability of insecticide metabolism and sensitivity in humans. His research group has cloned and sequenced the cDNA’s from humans, rabbits, and mice that encode paraoxonase (PON1) an HDL-associated enzyme that inactivates the toxic metabolites of several toxic organophosphate pesticides and nerve agents. The molecular basis of the genetic polymorphism in humans that specifies high or low metabolism has been identified. Dr. Furlong has worked closely with Dr. Lucio Costa in developing a mouse model that has provided valuable information on the role of PON1 in protecting against insecticide exposure.

Recently Dr. Nickerson (Genome Sciences, UW) sequenced the PON1 genes of more than forty individuals and identified close to 200 new polymorphisms. The role of this enzyme in lipid metabolism is also being investigated. A collaborative effort with Dr. Gail Jarvik has shown that low plasma levels of PON1 are a risk factor for carotid artery disease. Since the PON1 family of enzymes appear to play an important role in protecting against oxidative stress, the role of these enzymes as risk factors for other diseases is also being investigated.

A second area of interest is the development of biosensors that have applications in medicine and environmental monitoring. They have developed a fully portable surface plasmon resonance (SPR)-based sensor system that can monitor up to 24 analytes at a time. 

Selected Publications

Shih, D.M., Gu, L., Y.-R. Xia, M. Mavab, W.-F. Li, S. Hama, L.W. Castellani, C.E. Furlong, L.G. Costa, A.M. Fogelman and A.J. Lusis. 1998. Serum paraoxonase knockout mice are susceptible to organophosphate insecticides and lipoprotein oxidation. Nature 394: 284-287.

Li, W.-F., L.G. Costa and C.E. Furlong. 1997. Paraoxonase (Pon1) gene in mice: sequencing, chromosomal location, and developmental expression. Pharmacogenet. 7: 137-144.

Davies, H., R.J. Richter, M. Keifer, C. Broomfield, J. Sowalla and C.E. Furlong. 1996. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nature Genetics 14: 334-336.

Humbert, R., D.A. Adler, C.M. Disteche, C. Hassett, C.J. Omiecinski, and C.E. Furlong. 1993. The molecular basis of the human serum paraoxonase activity polymorphism. Nat. Genet. 3: 73-76.

Furlong, C.E. and J.A. Sundstrom. 1989. Immobilized cell bioreactors for producing immobilized protein bioreactors. Developments in Indust. Microbiol. 30: 141-148.
(J. Industrial Micro., Suppl. No. 4)

additional publication listings available via PubMed