Metnase mediates chromosome decatenation in acute leukemia cells

Justin Wray, Elizabeth A. Williamson, Sheema Sheema, Suk Hee Lee, Edward Libby, Cheryl L. Willman, Jac A. Nickoloff, Robert Hromas

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

After DNA replication, sister chromatids must be untangled, or decatenated, before mitosis so that chromatids do not tear during anaphase. Topoisomerase IIα (Topo IIα) is the major decatenating enzyme. Topo IIα inhibitors prevent decatenation, causing cells to arrest during mitosis. Here we report that acute myeloid leukemia cells fail to arrest at the mitotic decatenation checkpoint, and their progression through this checkpoint is regulated by the DNA repair component Metnase (also termed SETMAR). Metnase contains a SET histone methylase and transposase nuclease domain, and is a component of the nonhomologous endjoining DNA double-strand break repair pathway. Metnase interacts with Topo IIα and enhances its decatenation activity. Here we show that multiple types of acute leukemia cells have an attenuated mitotic arrest when decatenation is inhibited and that in an acute myeloid leukemia (AML) cell line this is mediated by Metnase. Of further importance, Metnase permits continued proliferation of theseAMLcells even in the presence of the clinical Topo IIα inhibitor VP-16. In vitro, purified Metnase prevents VP-16 inhibition of Topo IIα decatenation of tangled DNA. Thus, Metnase expression levels may predict AML resistance to Topo IIα inhibitors, and Metnase is a potential therapeutic target for small molecule interference.

Original languageEnglish (US)
Pages (from-to)1852-1858
Number of pages7
JournalBlood
Volume114
Issue number9
DOIs
StatePublished - Nov 20 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Wray, J., Williamson, E. A., Sheema, S., Lee, S. H., Libby, E., Willman, C. L., Nickoloff, J. A., & Hromas, R. (2009). Metnase mediates chromosome decatenation in acute leukemia cells. Blood, 114(9), 1852-1858. https://doi.org/10.1182/blood-2008-08-175760