Clearing trapped topoisomerases: processing modules, route selection, and responses to topoisomerase poisons

Topoisomerase poisons - the camptothecins, and the topoisomerase II poisons etoposide and doxorubicin - remain frontline anticancer drugs, and their efficacy depends less on how efficiently they trap topoisomerases than on how the cell handles the resulting topoisomerase DNA-protein crosslinks (TOP-DPCs). Five operations act on these lesions: ATP-dependent eviction of the intact complex by RAD54L2 with ZATT/ZNF451, which avoids the lesion rather than repairing it; reduction of the protein bulk by the proteasome and by the DNA-dependent proteases SPRTN, GCNA, DDI2 and FAM111A, directed by SUMOylation and by neddylated cullin-RING ligases; hydrolysis of the phosphotyrosyl bond by TDP1 and TDP2; incision of the flanking DNA by MRN-CtIP, MUS81-EME1, XPF-ERCC1 and FEN1; and export of the trapped enzyme to the lysosome by TEX264. The cell combines these modules into three routes that differ in what they leave behind. We review the evidence that lesion chemistry, lesion burden, replication and transcription context, the post-translational code and genotype determine which route is used, and compare the three for DNA loss, break intermediates, downstream requirements, cell-cycle restriction and mutational cost. We distinguish avoidance of the lesion, clearance of the trapped protein and resolution of an intact duplex, and note that for the export route only clearance has been demonstrated.