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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. | ||
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| + | 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. | ||
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| + | 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. <ref> “mAMSA resistant human topoisomerase IIβ mutation G465D has reduced ATP hydrolysis activity” Oxford JournalsLife Sciences Nucleic Acids Research Volume 34, Issue 5Pp. 1597-1607. [http://nar.oxfordjournals.org/content/34/5/1597 DOI: 10.1093/nar/gkl057]</ref> | ||
Revision as of 17:27, 24 September 2012
Human 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]
Crystal structure of a large fragment of human type II topoisomerases (TOP2) complexed to DNA and to the anticancer drug etoposide to reveal structural details of drug-induced stabilization of a cleavage complex[2].
The interplay between the , the , and the drug explains the structure-activity relations of etoposide derivatives and the molecular basis of drug-resistant mutations.
Also, at the we can see the , and both , and of the .
References
- ↑ “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
