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TOPs

Sunday 26 March 2006

Topoisomerases control DNA structure by maintaining the correct superhelical state within the cell, as well as by resolving intertwined DNA strands. This requires the formation of transient breaks in DNA.

Topoisomerase I (TOP1) generates single-stranded breaks, and topoisomerase II (TOP2A and TOP2B) introduces double-stranded breaks.

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TOP1
TOP2s TOP2A TOP2B
TOP3s TOP3A TOP3B

Topoisomerase inhibitors (topoisomerase poisons)

The cytotoxicity of topoisomerase I and II poisons is due to stabilization of the enzyme-DNA covalent cleavage intermediates, which are referred to as cleavage complexes.

Compounds that simply block access of topoisomerases to DNA do not show clinical efficacy; however, compounds that trap an intermediate in which the protein is covalently bound to DNA result in potent cytotoxicities when they subsequently encounter a replication fork or some other DNA processing event.

Clinically effective drugs that are believed to show their cytotoxicities through this mechanism include topotecan and SN-38 (topoisomerase I), and doxorubicin and mitoxantrone (topoisomerase II).

The cleavage complexes are reversible once the topoisomerase poisons dissociate from the ternary topoisomerase-DNA-drug complex, so residence time of the drug within the ternary complex is an important criterion for drug efficacy.

In contrast to doxorubicin, which binds to DNA even in the absence of topoisomerase II, etoposide (VP-16) does not bind to DNA in the absence of topoisomerase II, and therefore does not interfere with other processes that occur on DNA (for example, transcription and replication).

Pathology of the topoisomerase system

- germline mutations in the gene for topoisomerase I-binding RS protein (TOPORS) in autosomal dominant retinitis pigmentosa (adRP) linked to chromosome 9p21.1 (locus RP31) (17924349)

Videos

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Associated proteins

- TOPORS (toposiomerase 1-binding arginine/serine-rich protein)
- TOP1MT (mitochondrial topoisomerase 1)
- TOPBP1
- TRF4-2

References

- Cozzarelli NR, Cost GJ, Nollmann M, Viard T, Stray JE. Giant proteins that move DNA: bullies of the genomic playground. Nat Rev Mol Cell Biol. 2006 Aug;7(8):580-8. PMID: 16936698