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The mechanism of DNA generation breaks upon irinotecan exposure. Normal function of Top1: ① supercoiled sensing and nick development by Top1 leads to ② relaxation, then ③ Top1 re-ligates the nicked backbone and leaves the site. In the case of irinotecan exposure, Top1 gets covalently crosslinked to DNA, then ④ ligation of 3′-OH free end is blocked, which could translate into ⑤ double strand break and facilitate cytotoxicity.
