Frankenberg-Schwager Marlis, Kirchermeier Dorothea, Greif Goetz, Baer Karin, Becker Manuela, Frankenberg Dieter
Universitaet Goettingen, Zentrum Radiologie, Abteilung Nuklearmedizin, Von-Siebold-Str. 3, D-37075 Goettingen, Germany.
Toxicology. 2005 Sep 1;212(2-3):175-84. doi: 10.1016/j.tox.2005.04.015.
DNA double-strand breaks (DSBs) are formed during the processing of DNA interstrand crosslinks in replicating yeast and Chinese hamster cells exposed to DNA crosslinkers such as psoralen plus UVA or nitrogen mustard. They were also detected in human cells after treatment with photoactivated psoralen or mitomycin C. In contrast, no DSBs were observed after exposure of Chinese hamster cells to cisplatin, another crosslinking agent widely used for the therapy of various cancers, challenging a common role for DSBs in the processing of DNA interstrand crosslinks. Here we report for the first time that cisplatin-mediated DSBs are induced in replicating but not quiescent cells of the yeast Saccharomyces cerevisiae. When the main pathway of repair of DSBs is inhibited, these breaks accumulate in replicating cells. Thus it appears that DNA interstrand crosslinks induced by different crosslinking agents, including cisplatin, are processed yielding DSBs as an intermediate lesion. In stationary cells, however, removal of DNA interstrand crosslinks after cisplatin treatment occurs without the formation of DSBs. These findings point to an altered mode of processing of cisplatin-DNA adducts in replicating versus quiescent cells.
在暴露于补骨脂素加紫外线A或氮芥等DNA交联剂的复制酵母和中国仓鼠细胞中，DNA链间交联处理过程中会形成DNA双链断裂（DSB）。在用光活化补骨脂素或丝裂霉素C处理后的人类细胞中也检测到了DSB。相比之下，将中国仓鼠细胞暴露于顺铂（另一种广泛用于各种癌症治疗的交联剂）后，未观察到DSB，这对DSB在DNA链间交联处理中的常见作用提出了挑战。在此，我们首次报告顺铂介导的DSB在酿酒酵母的复制细胞而非静止细胞中被诱导。当DSB的主要修复途径受到抑制时，这些断裂会在复制细胞中积累。因此，似乎包括顺铂在内的不同交联剂诱导的DNA链间交联在处理过程中会产生DSB作为中间损伤。然而，在静止细胞中，顺铂处理后DNA链间交联的去除过程中不会形成DSB。这些发现表明，在复制细胞与静止细胞中，顺铂-DNA加合物的处理方式有所不同。
