monastrol and Chromosomal-Instability

Whereas germline-inherited whole-chromosome aneuploidy has long been known to cause miscarriages and developmental abnormalities, somatically acquired aneuploidies have been observed in cancer cells and more recently also in cells of the normal liver and brain. Furthermore, aneuploidy is being increasingly reported in clinical isolates of pathogenic microbes such as fungi and parasites. Whereas many efforts have been devoted to the dissection of the molecular mechanisms that lead to aneuploidy, we have only recently started to investigate how aneuploidy alters the phenotypic makeup of a cell. Here we review recent evidence supporting the idea that aneuploidy is a large-effect mutation that introduces large changes in the cellular phenome. From a systems biology perspective, this can be explained by the extensive changes that aneuploidy brings about in both the transcriptome and the proteome of a cell. We further provide an evolutionary perspective on how aneuploidy-induced phenotypic variation may contribute to the exacerbation of human pathologies such as cancer and infectious diseases, by conferring selectable traits such as increased virulence and drug resistance.

Topics: Aneuploidy; Animals; Biological Evolution; Chromosomal Instability; Chromosome Segregation; Disease; Humans; Karyotype; Mitosis; Neoplasms; Phenotype; Proteome; Pyrimidines; Stochastic Processes; Systems Biology; Thiones; Transcriptome

During mitosis, equal segregation of chromosomes depends on proper kinetochore-microtubule attachments. Merotelic kinetochore orientation, in which a single kinetochore binds microtubules from both spindle poles [1], is a major cause of chromosome instability [2], which is commonly observed in solid tumors [3, 4]. Using the fission yeast Schizosaccharomyces pombe, we show that a proper force balance between kinesin motors on interpolar spindle microtubules is critical for correcting merotelic attachments. Inhibition of the plus-end-directed spindle elongation motors kinesin-5 (Cut7) and kinesin-6 (Klp9) reduces spindle length, tension at kinetochores, and the frequency of merotelic attachments. In contrast, merotely is increased by deletion of the minus-end-directed kinesin-14 (Klp2) or overexpression of Klp9. Also, Cdk1 regulates spindle elongation forces to promote merotelic correction by phosphorylating and inhibiting Klp9. The role of spindle elongation motors in merotelic correction is conserved, because partial inhibition of the human kinesin-5 homolog Eg5 using the drug monastrol reduces spindle length and lagging chromosome frequency in both normal (RPE-1) and tumor (CaCo-2) cells. These findings reveal unexpected links between spindle forces and correction of merotelic attachments and show that pharmacological manipulation of spindle elongation forces might be used to reduce chromosome instability in cancer cells.

Topics: CDC2 Protein Kinase; Cell Cycle Proteins; Cell Line; Chromosomal Instability; Chromosomal Proteins, Non-Histone; Chromosome Segregation; Humans; Kinesins; Kinetochores; Microtubules; Nuclear Proteins; Phosphorylation; Protein Tyrosine Phosphatases; Pyrimidines; Schizosaccharomyces; Schizosaccharomyces pombe Proteins; Spindle Apparatus; Thiones

Various types of chromosomal aberrations, including numerical (aneuploidy) and structural (e.g., translocations, deletions), are commonly found in human tumors and are linked to tumorigenesis. Aneuploidy is a direct consequence of chromosome segregation errors in mitosis, whereas structural aberrations are caused by improperly repaired DNA breaks. Here, we demonstrate that chromosome segregation errors can also result in structural chromosome aberrations. Chromosomes that missegregate are frequently damaged during cytokinesis, triggering a DNA double-strand break response in the respective daughter cells involving ATM, Chk2, and p53. We show that these double-strand breaks can lead to unbalanced translocations in the daughter cells. Our data show that segregation errors can cause translocations and provide insights into the role of whole-chromosome instability in tumorigenesis.

Topics: Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cell Line; Cell Line, Tumor; Checkpoint Kinase 2; Chromosomal Instability; Chromosome Aberrations; Chromosome Segregation; Cytokinesis; DNA Breaks, Double-Stranded; DNA-Binding Proteins; Histones; Humans; Intracellular Signaling Peptides and Proteins; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Pyrimidines; Thiones; Translocation, Genetic; Tumor Suppressor p53-Binding Protein 1; Tumor Suppressor Protein p53; Tumor Suppressor Proteins