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 Citations (Scopus)

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
Pages (from-to)1852-1858
Number of pages7
JournalBlood
Volume114
Issue number9
DOIs
StatePublished - 2009

Fingerprint

Topoisomerase II Inhibitors
Type II DNA Topoisomerase
Chromosomes
Acute Myeloid Leukemia
Leukemia
Chromatids
Etoposide
Myeloid Cells
Mitosis
DNA
M Phase Cell Cycle Checkpoints
Transposases
Anaphase
Repair
Double-Stranded DNA Breaks
DNA Replication
Tears
DNA Repair
Cell Line
Cells

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Wray, J., Williamson, E. A., Sheema, S., Lee, S-H., Libby, E., Willman, C. L., ... 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

Metnase mediates chromosome decatenation in acute leukemia cells. / Wray, Justin; Williamson, Elizabeth A.; Sheema, Sheema; Lee, Suk-Hee; Libby, Edward; Willman, Cheryl L.; Nickoloff, Jac A.; Hromas, Robert.

In: Blood, Vol. 114, No. 9, 2009, p. 1852-1858.

Research output: Contribution to journalArticle

Wray, J, Williamson, EA, Sheema, S, Lee, S-H, Libby, E, Willman, CL, Nickoloff, JA & Hromas, R 2009, 'Metnase mediates chromosome decatenation in acute leukemia cells', Blood, vol. 114, no. 9, pp. 1852-1858. https://doi.org/10.1182/blood-2008-08-175760
Wray J, Williamson EA, Sheema S, Lee S-H, Libby E, Willman CL et al. Metnase mediates chromosome decatenation in acute leukemia cells. Blood. 2009;114(9):1852-1858. https://doi.org/10.1182/blood-2008-08-175760
Wray, Justin ; Williamson, Elizabeth A. ; Sheema, Sheema ; Lee, Suk-Hee ; Libby, Edward ; Willman, Cheryl L. ; Nickoloff, Jac A. ; Hromas, Robert. / Metnase mediates chromosome decatenation in acute leukemia cells. In: Blood. 2009 ; Vol. 114, No. 9. pp. 1852-1858.
@article{846353d3ead94aca8825995af8370123,
title = "Metnase mediates chromosome decatenation in acute leukemia cells",
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.",
author = "Justin Wray and Williamson, {Elizabeth A.} and Sheema Sheema and Suk-Hee Lee and Edward Libby and Willman, {Cheryl L.} and Nickoloff, {Jac A.} and Robert Hromas",
year = "2009",
doi = "10.1182/blood-2008-08-175760",
language = "English",
volume = "114",
pages = "1852--1858",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "9",

}

TY - JOUR

T1 - Metnase mediates chromosome decatenation in acute leukemia cells

AU - Wray, Justin

AU - Williamson, Elizabeth A.

AU - Sheema, Sheema

AU - Lee, Suk-Hee

AU - Libby, Edward

AU - Willman, Cheryl L.

AU - Nickoloff, Jac A.

AU - Hromas, Robert

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=70349263952&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349263952&partnerID=8YFLogxK

U2 - 10.1182/blood-2008-08-175760

DO - 10.1182/blood-2008-08-175760

M3 - Article

VL - 114

SP - 1852

EP - 1858

JO - Blood

JF - Blood

SN - 0006-4971

IS - 9

ER -