Cisplatin-mediated DNA double-strand breaks in replicating but not in quiescent cells of the yeast Saccharomyces cerevisiae

Abstract

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.