William Saunders, PhD
Associate Professor
Dept. of Biological Sciences
PhD, 1991, Johns Hopkins University
Email: wsaund@pitt.edu
Research Interest:
The research of the Saunders lab is focused on the study of cell division and the origin of divisional defects in cancer cells. When cells divide, it is essential that the components of the cell are separated such that both daughters will inherit the necessary starting material to propagate as healthy cells. During tumorigenesis, cells often divide irregularly with missegregation of chromosomes and microtubule organizing centers or centrosomes. Our interests are to define pathways required for normal division and determine how these pathways are altered in human disease.
Currently, we are focused on three types of abnormal division in tumor cells. These are multipolar spindles, anaphase bridges and failed cytokinesis.
Multipolar spindles happen when the cell tries to divide the chromosomes into more than two groups. This is a result of amplification of the number of centrosomes in the cell. Centrosomes organize the microtubules into a spindle to separate the chromosomes into two groups. Extra centrosomes can form more than two microtubule foci resulting in abnormal separation of the chromosomes into three or more groups. In cancer cells, multipolarity is accompanied by interference with the microtubule motor called cytoplasmic dynein. Dynein is not visible on cancer cell spindles and inhibition of dynein can greatly increase the multipolarity resulting from centrosomal amplification. In some tumor cells, dynein is inhibited by overexpression of another spindle motor called NuMA [1]. Current work in the lab is directed towards studying the mechanism of NuMA inhibition of dynein in vitro.
A related question is how the centrosomes get amplified in the first place. Currently, two models are proposed. One is that centrosomes are amplified by increased replication, the other is that centrosomes are amplified by failed cell division or cytokinesis. We have examined this question in cancer cells using live-cell imaging. In the cell lines examined, centrosomal amplification was associated with failure of cytokinesis. Recent work in the lab has shown that cytokinesis in cancer cells is due to a reduction of myosin heavy chain phosphorylation.
The third divisional defects of cancer cells we study is anaphase bridges. These structures form following DNA double-strand breaks and result in a tug-of-war between two dividing cells for a single chromosome [2]. Our focus is to identify the DNA repair pathways required for bridge formation. There are two known double-strand break repair pathways, nonhomologous end joining and homologous recombination, and we are testing mutants and siRNA knockdown of both pathways to examine their role in bridge induction.
A specialized type of cell division that is also defective in disease is meiosis. We study meiotic division in the model organism Saccharomyces cerevisiae, or budding yeast. We have used functional genomic analysis of a large collection of single gene deletion mutants created by a consortium of labs to identify many of the genes required for meiosis. Currently, we are examining the relationship between these gene products to define the pathways used to signal the start of meiosis. Defects in this pathway may contribute to birth defects in humans.
Recent Publication
Parikh, R.A., J.S. White, X. Huang, D.W. Schoppy, B.E. Baysal, R. Baskaran, C.J. Bakkenist, W.S. Saunders, L.C. Hsu, M. Romkes, and S.M. Gollin (2007) Loss of distal 11q is associated with DNA repair deficiency and reduced sensitivity to ionizing radiation in head and neck squamous cell carcinoma. Gene Chromosome Canc. 46:761-775
Acilan, C., D.M. Potter, and W.S. Saunders (2007) DNA repair pathways involved in anaphase bridge formation. Gene Chromosome Canc. 46:522-531
Reshmi, S.C., S. Roychoudhury, Z. Yu, E. Feingold, D. Potter, W.S. Saunders, and S.M. Gollin (2007) Inverted duplication pattern in anaphase bridges confirms the breakage-fusion-bridge (BFB) cycle model for 11q13 amplification. Cytogenet. Genome Res. 116:46-52
Reshmi, S.C., X. Huang, D.W. Schoppy, R.C. Black, W.S. Saunders, D.I. Smith, and S.M. Gollin (2007) Relationship between FRA11F and 11q13 gene amplification in oral cancer. Gene Chromosome Canc. 46:143-154
Mondal, G., S. Sengupta, C.K. Panda, C.K. Gollin, W.S. Saunders, and S. Roychoudhury (2007) Overexpression of Cdc20 leads to impairment of the spindle assembly checkpoint and aneuploidization in oral cancer. Carcinogenesis 28:81-92
Saunders, W. (2005) Centrosomal amplification and spindle multipolarity in cancer cells. Semin. Cancer Biol. 15:25-32
Sproul, L.R., D.J. Anderson, A.T. Mackey, W.S. Saunders, and S.P. Gilbert (2005) Cik1 targets the minus-end kinesin depolymerase Kar3 to microtubule plus ends. Curr. Biol. 15:1420-1427
Quintyne, N.J., J.E. Reing, D.R. Hoffelder, S.M. Gollin, and W.S. Saunders (2005) Spindle multipolarity is prevented by centrosomal clustering. Science 307:127-129
