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Nucleic Acids Research Advance Access originally published online on September 12, 2008
Nucleic Acids Research 2008 36(18):5822-5831; doi:10.1093/nar/gkn560
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Nucleic Acids Research, 2008, Vol. 36, No. 18 5822-5831
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genome integrity, repair and replication

The SET and transposase domain protein Metnase enhances chromosome decatenation: regulation by automethylation

Elizabeth A. Williamson1, Kanwaldeep Kaur Rasila1, Lori Kwan Corwin1, Justin Wray1, Brian D. Beck2, Virginia Severns3, Charlotte Mobarak3, Suk-Hee Lee2, Jac A. Nickoloff4 and Robert Hromas1,4,*

1Division of Hematology–Oncology, Cancer Research and Treatment Center, Department of Medicine, University of New Mexico Health Science Center, Albuquerque, NM 87131, 2Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, 3Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine and 4Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA

*To whom correspondence should be addressed. Tel: +1 505 272 5837; Fax: +1 505 272 5865; Email: rhromas{at}salud.unm.edu

Received May 16, 2008. Revised August 18, 2008. Accepted August 19, 2008.

Metnase is a human SET and transposase domain protein that methylates histone H3 and promotes DNA double-strand break repair. We now show that Metnase physically interacts and co-localizes with Topoisomerase II{alpha} (Topo II{alpha}), the key chromosome decatenating enzyme. Metnase promotes progression through decatenation and increases resistance to the Topo II{alpha} inhibitors ICRF-193 and VP-16. Purified Metnase greatly enhanced Topo II{alpha} decatenation of kinetoplast DNA to relaxed circular forms. Nuclear extracts containing Metnase decatenated kDNA more rapidly than those without Metnase, and neutralizing anti-sera against Metnase reversed that enhancement of decatenation. Metnase automethylates at K485, and the presence of a methyl donor blocked the enhancement of Topo II{alpha} decatenation by Metnase, implying an internal regulatory inhibition. Thus, Metnase enhances Topo II{alpha} decatenation, and this activity is repressed by automethylation. These results suggest that cancer cells could subvert Metnase to mediate clinically relevant resistance to Topo II{alpha} inhibitors.


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