The chemotherapy drug Cisplatin (cis-diamminedichloroplatinum(II)) induces crosslinks within and between DNA strands, and between DNA and nearby proteins. Therefore, Cisplatin-treated cells which progress into cell division may do so with altered chromosome mechanical properties. This could have important consequences for the successful completion of mitosis. Using Total Internal Reflection Fluorescence microscopy of live Cisplatin-treated Saccharomyces cerevisiae cells, we found that metaphase mitotic spindles have disorganized kinetochores relative to untreated cells, and also that there is increased variability in the chromosome stretching distance between sister centromeres. This suggests that chromosome stiffness may become more variable after Cisplatin treatment. We explored the effect of variable chromosome stiffness during mitosis using a stochastic model in which kinetochore microtubule dynamics were regulated by tension imparted by stretched sister chromosomes. Consistent with experimental results, increased variability of chromosome stiffness in the model led to disorganization of kinetochores in simulated metaphase mitotic spindles. Furthermore, the variability in simulated chromosome stretching tension was increased as chromosome stiffness became more variable. Because proper chromosome stretching tension may serve as a signal that is required for proper progression through mitosis, tension variability could act to impair this signal and thus prevent proper mitotic progression. Our results suggest a possible mitotic mode of action for the anti-cancer drug Cisplatin.
Bibliographical noteFunding Information:
We thank the Gardner, Duncan Clarke, Meg Titus and Gant Luxton lab members for useful discussions. This work was supported by the Pew Scholars Program in the Biomedical Sciences (supported by the Pew Charitable Trusts) (M.K.G.) and National Institutes of Health grant GM103833 (M.K.G.). J.M.C. was supported in part by a Postdoctoral Fellowship #124521-PF-13-109-01-CCG from the American Cancer Society.
- Chromosome stiffness
- Stochastic modeling