Dalton W Brian, Nandan Mandayam O, Moore Ryan T, Yang Vincent W
Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Cancer Res. 2007 Dec 15;67(24):11487-92. doi: 10.1158/0008-5472.CAN-07-5162.
The mitotic checkpoint is a mechanism that arrests the progression to anaphase until all chromosomes have achieved proper attachment to mitotic spindles. In cancer cells, satisfaction of this checkpoint is frequently delayed or prevented by various defects, some of which have been causally implicated in tumorigenesis. At the same time, deliberate induction of mitotic arrest has proved clinically useful, as antimitotic drugs that interfere with proper chromosome-spindle interactions are effective anticancer agents. However, how mitotic arrest contributes to tumorigenesis or antimitotic drug toxicity is not well defined. Here, we report that mitotic chromosomes can acquire DNA breaks during both pharmacologic and genetic induction of mitotic arrest in human cancer cells. These breaks activate a DNA damage response, occur independently of cell death, and subsequently manifest as karyotype alterations. Such breaks can also occur spontaneously, particularly in cancer cells containing mitotic spindle abnormalities. Moreover, we observed evidence of some breakage in primary human cells. Our findings thus describe a novel source of DNA damage in human cells. They also suggest that mitotic arrest may promote tumorigenesis and antimitotic toxicity by provoking DNA damage.
有丝分裂检查点是一种机制，它会阻止细胞进入后期，直到所有染色体都正确附着到有丝分裂纺锤体上。在癌细胞中，这个检查点的满足常常会因各种缺陷而延迟或受阻，其中一些缺陷已被证明与肿瘤发生有因果关系。同时，故意诱导有丝分裂停滞已被证明在临床上是有用的，因为干扰染色体与纺锤体正常相互作用的抗有丝分裂药物是有效的抗癌剂。然而，有丝分裂停滞如何导致肿瘤发生或抗有丝分裂药物毒性尚不清楚。在此，我们报告在人类癌细胞中，在药物诱导和基因诱导有丝分裂停滞过程中，有丝分裂染色体都可能获得DNA断裂。这些断裂激活DNA损伤反应，独立于细胞死亡发生，随后表现为核型改变。这种断裂也可能自发发生，特别是在含有有丝分裂纺锤体异常的癌细胞中。此外，我们在原代人类细胞中也观察到了一些断裂的证据。因此，我们的发现描述了人类细胞中一种新的DNA损伤来源。它们还表明，有丝分裂停滞可能通过引发DNA损伤来促进肿瘤发生和抗有丝分裂毒性。
