Analysis and Modeling of Chromosome Congression During Mitosis in the Chemotherapy Drug Cisplatin.
Analysis and Modeling of Chromosome Congression During Mitosis in the Chemotherapy Drug Cisplatin.
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DOI：
10.1007/s12195-013-0306-7
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发表时间：
2013-12-01
影响因子：
2.8
通讯作者：
Gardner, Melissa K.
中科院分区：
文献类型：
--
作者：
Chacon, Jeremy M.;Gardner, Melissa K.
化疗药物顺铂（顺式二氨二氯铂（II））诱导DNA链内部和之间以及DNA与附近蛋白质之间的交联。因此，顺铂处理的细胞进入细胞分裂可能会改变染色体的机械特性。这可能对有丝分裂的成功完成产生重要影响。使用全内反射荧光（TIRF）显微镜活顺铂处理的酿酒酵母细胞，我们发现，中期有丝分裂纺锤体有混乱的着丝粒相对于未处理的细胞，也有增加的变异性姐妹着丝粒之间的染色体拉伸距离。这表明顺铂治疗后染色体刚度可能变得更加可变。我们探讨了可变的染色体刚度在有丝分裂过程中使用的随机模型，其中动粒微管动力学调节拉伸姐妹染色体所赋予的张力的影响。与实验结果一致，增加模型中染色体刚度的变异性导致模拟中期有丝分裂纺锤体中动粒的解体。此外，在模拟染色体拉伸张力的变异性增加，染色体刚度变得更加多变。因为适当的染色体拉伸张力可以作为通过有丝分裂的适当进展所需的信号，张力变异性可以起到损害该信号的作用，从而阻止适当的有丝分裂进展。我们的研究结果表明，抗癌药物顺铂的作用可能是有丝分裂模式。
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 (TIRF) 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.
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影响因子：
21.3
作者：
Bakhoum, Samuel F.;Thompson, Sarah L.;Manning, Amity L.;Compton, Duane A.
通讯作者：
Compton, Duane A.
影响因子：
4.3
作者：
Cimini, Daniela
通讯作者：
Cimini, Daniela
影响因子：
9.2
作者：
Gerlich, Daniel;Koch, Birgit;Ellenberg, Jan
通讯作者：
Ellenberg, Jan
DOI：
10.1083/jcb.200910085
发表时间：
2010-03-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kawamura R;Pope LH;Christensen MO;Sun M;Terekhova K;Boege F;Mielke C;Andersen AH;Marko JF
通讯作者：
Marko JF
DOI：
10.1016/s0921-8777(99)00011-7
发表时间：
1999-05-14
期刊：
MUTATION RESEARCH-DNA REPAIR
影响因子：
--
作者：
Grossmann, KF;Brown, JC;Moses, RE
通讯作者：
Moses, RE