“Inhibition of an enzyme that alters DNA topology with an anticancer agent should facilitate development of better cancer drugs.” --Science.

Summary of the Science paper

Type II topoisomerases (TOP2s) are ubiquitous enzymes that play essential roles in cellular DNA transactions including replication, transcription, recombination, and chromosome condensation and segregation. These two-fold symmetric enzymes transiently cleave a pair of opposing phosphodiester bonds four base pairs apart, generating a TOP2-DNA cleavage complex. Passage of a second DNA segment through this enzyme-bridged “DNA gate” and its resealing complete the topological change of the DNA. TOP2’s DNA cleavage activity is a double-edged sword; failure to reseal the enzyme-mediated DNA break can lead to cell death. Several potent anticancer drugs, such as etoposide, doxorubicin, and mitoxantrone, exploit this harmful aspect of TOP2 and promote the formation of cytotoxic DNA lesions by increasing the steady-state level of cleavage complexes. Despite the extensive clinical use of these drugs, however, the lack of three-dimensional structures of any drug-stabilized cleavage complexes has left the structural bases of drug actions and resistance largely unresolved.

In the study recently published by Science, which is entitled “Structural Basis of Type II topoisomerase inhibition by the anticancer drug etoposide” (Science, Vol. 333, pages 459-462, 22 July 2011), the NTU researchers reported the crystal structure of a large fragment of human TOP2β (designated hTOP2βcore) complexed to DNA and to etoposide. This structure provides the first observations of TOP2 ternary cleavage complexes stabilized by anticancer drugs.

The high resolution structure of hTOP2βcore-DNA-etoposide ternary complex reveals the detailed interplays between protein, DNA and drug. Besides providing structural basis of drug action and resistance, this structure also offers molecular codes useful for the design of isoform-specific TOP2-targeting agent. This aspect is extremely important because all vertebrates possess two highly similar yet functionally distinct TOP2 isoforms. The α-isoform is particularly important for DNA replication and is usually present at high levels in fast growing cancer cells, whereas the β-isoform is mainly involved in transcription-related processes. Although the inhibition of both TOP2 isoforms contributes to the drug-induced death of cancer cells, targeting of the β-isoform has been implicated in deleterious therapy-related secondary malignancies. Therefore, it is desirable to develop the isoform-specific TOP2-targeting agents. The reported structure further reveals that, while most drug-contacting residues are conserved between isoforms, a key drug-interacting residue Q778 is replaced with methionine (M762) in the α-isoform. Such a change in residue polarity may be exploitable in developing new isoform-specific anticancer drugs with reduced side effects.

(http://www.sciencemag.org/content/333/6041.toc)