Topoisomerases are complex molecular machines that modulate DNA topology to maintain chromosome superstructure and integrity. Although capable of stand-alone activity in vitro, topoisomerases are frequently linked to larger pathways and systems that resolve specific DNA superstructures and intermediates arising from cellular processes such as DNA repair, transcription, replication and chromosome compaction. Topoisomerase activity is indispensible to cells, but requires the transient breakage of DNA strands. This property has been exploited, often for significant clinical benefit, by various exogenous agents that interfere with cell proliferation. Despite decades of study, surprising findings involving topoisomerases continue to emerge with respect to their cellular function, regulation and utility as therapeutic targets.
Topoisomerases are classified into several families, namely, types IA, IB, IC, IIA and IIB. These families have different cellular roles and preferential substrate specificities.
Topoisomerases are involved in a range of cellular nucleic acid transactions, including DNA replication, transcription, packaging, compaction, recombination and repair. Topoisomerases interact with various proteins in the cell to accomplish these tasks.
Post-translational modification of eukaryotic topoisomerases regulates their activation, localization and destruction.
Small molecules and proteins can inhibit topoisomerase activity at different stages of the topoisomerase catalytic cycle. Inhibition of topoisomerases has been exploited in therapeutics and in nature.
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The authors thank K. Drlica for thoughtful discussions and editing. This work was supported by a US National Science Foundation pre-doctoral fellowship (to S.M.V.) and the US National Cancer Institute (grant CA077373 to J.M.B.).
The authors declare no competing financial interests.
The result of duplex DNA twisting on itself in three-dimensional space.
Homologous genes separated by a duplication event that have evolved new functions.
- Domains of life
The three major evolutionary branches (Bacteria, Archaea and Eukarya) of modern-day cellular lineages.
- Negatively supercoiled DNA
DNA that is under-twisted (wound to <10.5 base pairs per turn). Negative supercoiling destabilizes the DNA, allowing complementary strands to be more easily denatured. By contrast, DNA becomes more resistant to denaturation when positively supercoiled (wound to >10.5 base pairs per turn).
- Superfamily 2 helicase
A member of a diverse group of ATP-dependent nucleic acid helicases and translocases that share a conserved domain architecture. Many members of this family can locally melt or unwind short duplex regions.
- Abasic lesions
Regions of DNA damage in which the nucleobase has been excised from the sugar backbone.
Topologically interlinked duplex DNA rings.
- Plectonemic supercoiling
The natural tendency of supercoiled DNA to wrap back on itself, forming intramolecularly wound structures known as plectonemes. Because DNA is itself a chiral molecule, negatively and positively supercoiled states cause the DNA to coil in opposite directions (in the form of right- and left-handed supertwists, respectively).
- Superhelical densities
Measurements of the over- or under-twistedness of DNA, generally expressed as the ratio by which the twist of the supercoiled state differs from that of the relaxed state.
- ATP-binding-cassette ATPases
(ABC ATPases). A family of proteins that include membrane-bound transporters, DNA repair factors and structural maintenance of chromosomes (SMC) proteins. ABC ATPases possess a conserved ATPase site that is often formed at dimer interfaces. ATP binding results in conformational changes (often dimerization) that affect the associated partner proteins and substrates.
A chromosomal site for replisome assembly.
- Origin recognition complex
A multisubunit protein complex that localizes to origins to initiate DNA replication in eukaryotes.
- Poly(ADP-ribose) polymerase 1
An enzyme that adds chains of ADP-ribose to proteins as a response to DNA damage and cell death.
Entangled daughter duplexes that are formed behind a replication fork during strand synthesis.
A junction between two double-stranded DNA molecules, in which one strand of one DNA molecule forms a duplex with the complementary strand on the other DNA molecule.
- Scissile phosphate
The phosphate at which a nucleic acid backbone is broken by nucleophilic attack.
- E3 ligases
Enzymes that attach ubiquitin or ubiquitin-like proteins to target proteins.
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Vos, S., Tretter, E., Schmidt, B. et al. All tangled up: how cells direct, manage and exploit topoisomerase function. Nat Rev Mol Cell Biol 12, 827–841 (2011) doi:10.1038/nrm3228
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