Metnase mediates chromosome decatenation in acute leukemia cells.
After DNA replication, sister chromatids must be untangled, or decatenated, before mitosis so that chromatids do not tear during anaphase. Topoisomerase IIalpha (Topo IIalpha) is the major decatenating enzyme. Topo IIalpha 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 end-joining DNA double-strand break repair pathway. Metnase interacts with Topo IIalpha 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 these AML cells even in the presence of the clinical Topo IIalpha inhibitor VP-16. In vitro, purified Metnase prevents VP-16 inhibition of Topo IIalpha decatenation of tangled DNA. Thus, Metnase expression levels may predict AML resistance to Topo IIalpha inhibitors, and Metnase is a potential therapeutic target for small molecule interference.
Wray
Justin
J
Division of Hematology-Oncology, Cancer Research and Treatment Center, Department of Medicine, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.
Williamson
Elizabeth A
EA
Sheema
Sheema
S
Lee
Suk-Hee
SH
Libby
Edward
E
Willman
Cheryl L
CL
Nickoloff
Jac A
JA
Hromas
Robert
R
D000951:Antigens, Neoplasm / Q000378:metabolism; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002875:Chromosomes / Q000648:ultrastructure*; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008938:Mitosis; D008954:Models, Biological
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D005047:Etoposide; D004247:DNA; D011495:Histone-Lysine N-Methyltransferase; C510450:SETMAR protein, human; D004250:DNA Topoisomerases, Type II