Abstract
Etoposide is a DNA topoisomerase 2-targeting drug widely used for the treatment of cancer. The cytoxicity of etoposide correlates with the generation of DNA double-strand breaks (DSBs), but the mechanism of how it induces DSBs in cells is still poorly understood. Catalytically, etoposide inhibits the re-ligation reaction of Top2 after it nicks the two strands of DNA, trapping it in a cleavable complex consisting of two Top2 subunits covalently linked to the 5’ ends of DNA (Top2cc). Top2cc is not directly recognized as a true DSB by cells because the two subunits interact strongly with each other to hold the two ends of DNA together. In this study we have investigated the cellular mechanisms that convert Top2ccs into true DSBs. Our data suggest that there are two mechanisms, one dependent on active replication and the other dependent on proteolysis and transcription. The relative contribution of each mechanism is affected by the concentration of etoposide. We also find that Top2α is the major isoform mediating the replication-dependent mechanism and both Top2α and Top2 mediate the transcription-dependent mechanism. These findings are potentially of great significance to the improvement of etoposide’s efficacy in cancer therapy.
Highlights
Etoposide (VP16) is one of the most widely used drugs for the treatment of various types of human malignancy, including leukemia, lymphoma, and solid tumors [1,2,3,4]
For Top2-DNA cleavable complex (Top2cc) to be recognized as a true double-strand breaks (DSBs), it has to be further processed by cells [2]
Cells treated with etoposide developed a large number of discrete subnuclear foci of replication protein A (RPA), the eukaryotic single-stranded DNA binding protein (Figure 1A)
Summary
Etoposide (VP16) is one of the most widely used drugs for the treatment of various types of human malignancy, including leukemia, lymphoma, and solid tumors [1,2,3,4]. Its efficacy varies significantly among different types of cancer It is associated with the serious side effect of secondary leukemia resulting from drug induced chromosome translocations [5,6]. Top2α is highly expressed in dividing cells and tumor cells, and further up-regulated during S and G2 phases [13,14,15] It is essential for cell proliferation, participating in replication, transcription, and chromosome structure and segregation [16]. Each subunit of Top nicks one strand of DNA to generate a double-strand break, through which another DNA passes, resulting in changes of topology [23]. The mechanism by which cells convert a Top2cc into a true DSB is still not well understood
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