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, 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.[less]
Figure 3: Multipolar mitosis in a tetraploid cell. Red: centrosomal marker, green: microtubules, blue: DNA. By Susana Godinho.
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.
Somewhat surprisingly, polyploidy is frequent in nature for example in fungi and plants. Some tissues in Metazoans contain polyploid cells at marked frequency that can increase upon some environmental cues and stresses. Yet, what advantages brings tetraploidy and polyploidy to the organisms? And how can Metazoans control the potential dangerous propagation of tetraploid cells that has been shown to facilitate tumorogenesis?
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.[less]
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.
Tetraploidy is thought to promote tumorigenesis by compromising genomic stability, thereby generating aneuploid cells – cells that contain imbalanced number of chromosome that differs from multiples of haploid chromosome set. Aneuploidy is detrimental in humans – it is recognized as the leading cause of spontaneous miscarriages and surviving infants suffer from multiple pathologies (e.g. in Down syndrome, trisomy of chromosome 21). Aneuploidy is also found in up to 70 % of malignant tumors. The consequences of aneuploidy and the reasons for the associated risks are poorly understood. To uncover the changes in human cells with aneuploid karyotype, we transfer individual chromosomes into human diploid and chromosomally stable cells. Comparison of the parental cell lines with isogenic cell lines that differ only by presence of one or a few extra chromosomes allows determining the direct consequences of aneuploidy.
Finally, to understand the routes to aneuploidy, we investigate the role of shugoshin (Sgo1), which is essential for faithful chromosome segregation. We found that Sgo1 localizes condensin to the centromeric chromatin. Failure to recruit condensin results in an abnormal conformation of the pericentric chromatin, impairs the mitotic error correction and leads to aneuploidy. Sgo1 is also required to maintain Aurora B on kinetochores during metaphase. Our findings determine shugoshin as a molecular adaptor governing chromosome biorientation.
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?
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