Structure of Enzyme Topoisomerase II Alpha Unravelled Providing Basis for More Accurate Design of Chemotherapeutic Drugs
Reports new study in Journal of Molecular Biology
The type II topoisomerases are important enzymes that are involved in maintaining the structure of DNA and chromosome segregation during both replication and transcription of DNA. One of these enzymes, topoisomerase II alpha, is involved in the replication of DNA and cell proliferation, and is highly expressed in rapidly dividing cancer cells. As such, this enzyme is the primary target of chemotherapeutic small molecule inhibitors such as etoposide. A major drawback to the use of these drugs is their association with secondary malignancies in some patients -- a side effect believed to be caused by a cross-reaction with topoisomerase II beta, another member of this family that is involved in DNA transcription.
In their study the group of researchers, led by Professor James Berger, report securing the structure of the active site core of topoisomerase II alpha in complex with DNA. They describe the conformational changes undergone by the enzyme during DNA binding and cleavage. While the structure of etoposide-inhibited topoisomerase II beta has been previously established by others, this is the first time similar structural information has been available for topoisomerase II alpha. Comparing the structures of these enzymes could assist in the design of more specific etoposide-like drugs, and reduce the risk of secondary malignancies.
“We hope this work will lead to an improved understanding of the mechanisms by which select small-molecule agents inhibit type II topoisomerase function, as well as help guide the development of new or improved antibacterial and anticancer drugs against enzymes of this class,” said Professor Berger.
In a commentary accompanying the article, Professor N. Patrick Higgins of the University of Alabama, states that, together with the previously published structure of topoisomerase II beta, “...these two structures provide key information that will be relevant to understanding how these closely related proteins perform different roles during cell growth and tissue development. The newly described structure could also provide the basis for the design of more selective drugs, with a lower risk of side effects.”
The article is “The Structure of DNA-Bound Human Topoisomerase II Alpha: Conformational Mechanisms for Coordinating Inter-Subunit Interactions with DNA Cleavage” by Timothy J. Wendorff, Bryan H. Schmidt, Pauline Heslop, Caroline A. Austin, and James M. Berger (doi:10.1016/j.jmb.2012.07.014). The article appears in Journal of Molecular Biology, Volume 424, Issue 3-4, pages 109–124 (7 December 2012), published by Elsevier.
# # #
Notes for editors
Full text of the article is available to credentialed journalists upon request; contact Meghan Jendrysik at +1 617 397 2845 or firstname.lastname@example.org. Journalists wishing to interview the authors may contact James Berger at +1 510 643 9483 or email@example.com.
About Journal of Molecular Biology
The Journal of Molecular Biology provides high quality, comprehensive and broad coverage in all areas of molecular biology. The journal publishes original scientific research papers that provide functional and mechanistic insights and report a significant advance to the field. The journal encourages the submission of multidisciplinary studies that use complementary experimental and computational approaches to address challenging biological questions. http://www.journals.elsevier.com/journal-of-molecular-biology/
Elsevier is a world-leading provider of information solutions that enhance the performance of science, health, and technology professionals, empowering them to make better decisions, deliver better care, and sometimes make groundbreaking discoveries that advance the boundaries of knowledge and human progress. Elsevier provides web-based, digital solutions — among them ScienceDirect, Scopus, Elsevier Research Intelligence,and ClinicalKey—and publishes over 2,200 journals, including The Lancet and Cell, and over 25,000 book titles, including a number of iconic reference works.
The company is part of Reed Elsevier Group PLC, a world leading provider of professional information solutions in the Science, Medical, Legal and Risk and Business sectors, which is jointly owned by Reed Elsevier PLC and Reed Elsevier NV. The ticker symbols are REN (Euronext Amsterdam), REL (London Stock Exchange), RUK and ENL (New York Stock Exchange).Media contact
+1 617 397 2845