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Human topoisomerase IIbeta in complex with DNA and etoposideHuman topoisomerase IIbeta in complex with DNA and etoposide
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The research team described the structural basis by which an anticancer drug etoposide (Vepesid) kills cancer cells by interacting with its cellular targets human DNA topoisomerase type II.
Type II topoisomerases (TOP2s) are abundant enzymes that play an essential role in DNA replication and transcription and are important targets for cancer chemotherapeutic drugs. These enzymes briefly cleave a pair of opposing phosphodiester bonds four base pairs apart, generating a TOP2-DNA cleavage complex.
TOP2’s DNA cleavage activity is usually referred to as 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. [1]
In this paper, the researchers reported on the crystal structure of a large fragment of type II human topoisomerases β (hTOP2β core) complexed to DNA and to the anticancer drug etoposide to reveal structural details of drug-induced stabilization of a cleavage complex[2]. This structure provided the first observation of a TOP2 ternary cleavage complex stabilized by an anticancer drug.
The high-resolution structure of the hTOP2βcore-DNA-etoposide ternary complex reveals the intricate interplays between , and drugs. Besides providing the structural basis of drug action and resistance, this structure also offers molecular codes useful for the design of isoform-specific TOP2-targeting agents. 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.
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ReferencesReferences
- ↑ “mAMSA resistant human topoisomerase IIβ mutation G465D has reduced ATP hydrolysis activity” Oxford JournalsLife Sciences Nucleic Acids Research Volume 34, Issue 5Pp. 1597-1607. DOI: 10.1093/nar/gkl057
- ↑ Wu CC, Li TK, Farh L, Lin LY, Lin TS, Yu YJ, Yen TJ, Chiang CW, Chan NL. Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide. Science. 2011 Jul 22;333(6041):459-62. PMID:21778401 doi:10.1126/science.1204117