Table 1 |.

Drugs, DNA alterations and physiological processes that lead to the formation of persistent TOPcc

Causes	Consequences for TOP1 enzymes	Consequences for TOP2 enzymes
Anticancer drugs acting as interfacial inhibitors155	Trapping of TOP1cc by irinotecan, topotecan, indenoisoquinolines* and tumour-targeting camptothecin derivatives3,154,155	Trapping of TOP2cc by etoposide, teniposide, doxorubicin, epirubicin, idarubicin and mitoxantrone4
Oxidative DNA lesions (8-oxoguanine, 8-oxoadenosine and 5-hydroxycytosine)	Induction and trapping of TOP1cc218,219	Induction and trapping of TOP2cc220
Abasic sites and DNA mismatches	Formation of irreversible TOP1cc221	Formation of irreversible TOP2cc220,222–225
Carcinogenic base adducts (methylated bases, exocyclic adducts, benzo[a]pyrene adducts and crotonaldehyde adducts)	Induction and trapping of TOP1cc226–232	Induction and trapping of TOP2cc220,233–235
Nicks and DNA strand breaks	Formation of irreversible TOP1cc, double-stranded breaks, genomic deletions and recombination18,167,168,236,237	Formation of irreversible TOP2cc235
UV lesions (pyrimidine dimers and 6.4-photoproducts)	Induction of TOP1cc238,239	Enzymatic inhibition240
Ribonucleotide incorporation into DNA	Formation of TOP1cc that generate nicks with 2′,3′-cyclic phosphate ends and short deletions in repeat sequences166–168	Stabilization of TOP2cc with asymmetrical cleavage20,169,241
Natural and food products	Unknown	Stabilization of TOP2cc by flavones, tea and wine products205
Genetic defects	Unrepaired TOP1cc due to TDP1 defects177,206,210 in cooperation with ATM defects179	Unrepaired TOP2cc due to TDP2 defects69
Transcription activation	Stabilization of TOP1cc at enhancers42	Stabilization of TOP2cc at promoters62,65,242,243

ATM, ataxia telangiectasia mutated; TDP, tyrosyl-DNA phosphodiesterase; TOPcc, topoisomerase cleavage complex.

^*Indenoisoquinoline derivatives are in clinical trials.