Research

Maintenance of genome stability is crucial for stable propagation of organisms. Recently, it has been shown that cells with increased ploidy (increased number of chromosome sets) have impaired ability to maintain genomic stability. For example, tetraploid budding yeast cells display high rates of chromosome loss. Moreover, it has been demonstrated that tetraploid mammary epithelial gland cells have increased tumorigenic potential when compared to their diploid counterparts. These observations support the idea that changes in ploidy have profound effects on genome stability, however, the underlying molecular mechanisms are not well understood.

Figure 3: Multipolar mitosis in a tetraploid cell. Red: centrosomal marker, green: microtubules, blue: DNA. By Susana Godinho.
Click on picture for details.

A genome-wide screen to identify genes required specifically for survival of yeast tetraploids revealed only 39 “ploidy-specific lethal” genes out of 3540 tested. Majority of these genes belong to one of the three pathways: homologous recombination, sister chromatid cohesion and mitotic spindle functions suggesting that these processes are impaired in cells with increased ploidy. Remarkably, these three pathways play an important role in maintenance of genome stability. This result can elucidate how increased ploidy alters physiology of a cell.

Figure 4: Diploid and tetraploid yeast cells. Although the cellular and nuclear volume increases, the size of a spindle remains constant. Red: nuclear envelope, green: microtubules.

The research will focus on following topics:

What is the mechanism of genomic instability in eukaryotic polyploids?
How can the altered physiology of polyploid cells contribute to tumor development?
What are the differences and similarities between polyploidy (increased number of chromosome sets) and aneuploidy (increased number of chromosomes frequently accompanied by chromosomal rearrangements)? Can aneuploidy result from polyploidy?

Related reading:

Andalis A.A., Storchova Z., Galitski T., Styles C., Pellman D., and Fink G.R. (2004) Polyploidy in Saccharomyces cerevisiae leads to stationary phase death. Genetics 167: 1109-1121.

Fujiwara, T., Bandhi M. et al. (2005) Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437, 1043-7.

Ganem N.J., Storchova Z., Pellman D. (2007) Tetraploidy, aneuploidy and cancer. Curr Opin Genet Dev 17: 157-162.

Mayer, V. W. & Aguilera, A. (1990) High levels of chromosome instability in polyploids of Saccharomyces cerevisiae. Mutat Res 231, 177-86.

Storchova Z., Breneman A., Cande J., Dunn J., Burbank K., O’Toole E., Pellman D. (2006) Genome-wide analysis of polyploidy in yeast: scaling effects and genome stability. Nature 443: 541-547.

Storchova Z., Pellman D. (2004) From polyploidy to aneuploidy, genome instability and cancer. Nat Rev Mol Cell Biol. 5:45-54.