DNA-damage response during mitosis induces whole-chromosome missegregation.
DNA-damage response during mitosis induces whole-chromosome missegregation.
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DOI：
10.1158/2159-8290.cd-14-0403
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发表时间：
2014-11
期刊：
影响因子：
28.2
通讯作者：
Compton DA
中科院分区：
文献类型：
--
作者：
Bakhoum SF;Kabeche L;Murnane JP;Zaki BI;Compton DA
许多癌症显示结构（s-CIN）和数量（w-CIN）染色体不稳定性。有丝分裂期间染色体分离缺陷已被证明会导致DNA损伤，从而诱导染色体结构重排（s-CIN）。相反，DNA损伤是否会破坏有丝分裂过程以产生全染色体不稳定性（w-CIN）尚不清楚。在这里，我们表明，在有丝分裂过程中的DNA损伤反应（DDR）的激活选择性地稳定着丝粒微管（K-MT）附件的染色体通过极光-A和Plk 1激酶，从而增加在后期落后的染色体的频率。抑制DDR蛋白，ATM或Chk 2，消除了DNA损伤对k-MT和染色体分离的影响，而在没有DNA损伤的情况下激活DDR足以诱导染色体分离错误。最后，在具有持续DNA损伤的癌细胞中在有丝分裂期间抑制DDR抑制固有的染色体分离缺陷。因此，有丝分裂期间的DDR不适当地稳定k-MT，从而在s-CIN和w-CIN之间建立联系。
Many cancers display both structural (s-CIN) and numerical (w-CIN) chromosomal instabilities. Defective chromosome segregation during mitosis has been shown to cause DNA damage that induces structural rearrangements of chromosomes (s-CIN). In contrast, whether DNA damage can disrupt mitotic processes to generate whole chromosomal instability (w-CIN) is unknown. Here we show that activation of the DNA damage response (DDR) during mitosis selectively stabilizes kinetochore-microtubule (k-MT) attachments to chromosomes through Aurora-A and Plk1 kinases, thereby increasing the frequency of lagging chromosomes during anaphase. Inhibition of DDR proteins, ATM or Chk2, abolishes the effect of DNA damage on k-MTs and chromosome segregation, whereas activation of the DDR in the absence of DNA damage is sufficient to induce chromosome segregation errors. Finally, inhibiting the DDR during mitosis in cancer cells with persistent DNA damage suppresses inherent chromosome segregation defects. Thus, DDR during mitosis inappropriately stabilizes k-MTs creating a link between s-CIN and w-CIN.