Topoisomerase 1 (Top1) and 2 (Top2) are common targets of anti-cancer drugs, which induce specific DNA lesions that are thought to lead to cell death in tumour cells. Camptothecin blocks DNA religation in the Top1–DNA complex and induces Top1-attached nick DNA lesions (Top1–DNA damage). We propose that nucleotide excision repair (NER) factors, excision repair cross complementing 1 protein-xeroderma pigmentosum group F (ERCC1–XPF) endonuclease, and replication protein A (RPA), participate in the repair of Top1-attached nick DNA lesions. ERCC1–XPF exhibits nuclease activity in the presence of RPA on a 3′-phosphotyrosyl bond nick-containing DNA (3′-Tyr-nick DNA) substrate, which mimics a Top1-attached nick DNA lesion. Moreover, repair of the 3′-Tyr-nick DNA occurred in the presence of NER factors, including ERCC1–XPF, RPA, DNA polymerase delta, flap endonuclease 1 (FEN1) and DNA ligase 1 (LIG1). We also illustrate a repair model for DNA lesions induced by Top2 inhibitor etoposide (VP-16), Top2-attached nick DNA (Top2-DNA damage). FEN1 participates in the cleavage of the 5′-phosphotyrosyl bond nick-containing DNA (5′-Tyr-nick DNA) substrates, which mimic Top2-attached nick DNA lesions. Under DNA repair synthesis conditions, FEN1 efficiently repaired the 5′-Tyr-nick DNA substrates in the presence of other base excision repair (BER) factors, LIG1 and DNA polymerase beta (POLB). Taken together, some of the NER and BER machinery might represent an alternative repair pathway for Top1- and Top2-DNA damage.
Topoisomerase TOPO damage Nucleotide excision repair Base excision repair
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I thank J. Yamamoto for technical assistance and suggestions.
This work was supported by a Grant-in-Aid for Scientific Research (B) 25281018 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.
Compliance with ethical standards
Conflict of interest
The author declare that there is no conflict of interest.
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