The SET and transposase domain protein Metnase enhances chromosome decatenation: regulation by automethylation.
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 IIalpha (Topo IIalpha), the key chromosome decatenating enzyme. Metnase promotes progression through decatenation and increases resistance to the Topo IIalpha inhibitors ICRF-193 and VP-16. Purified Metnase greatly enhanced Topo IIalpha 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 IIalpha decatenation by Metnase, implying an internal regulatory inhibition. Thus, Metnase enhances Topo IIalpha decatenation, and this activity is repressed by automethylation. These results suggest that cancer cells could subvert Metnase to mediate clinically relevant resistance to Topo IIalpha inhibitors.
Williamson
Elizabeth A
EA
Division of Hematology-Oncology, Cancer Research and Treatment Center, Department of Medicine, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.
Rasila
Kanwaldeep Kaur
KK
Corwin
Lori Kwan
LK
Wray
Justin
J
Beck
Brian D
BD
Severns
Virginia
V
Mobarak
Charlotte
C
Lee
Suk-Hee
SH
Nickoloff
Jac A
JA
Hromas
Robert
R
D000951:Antigens, Neoplasm / Q000378:metabolism*; D002460:Cell Line; D002877:Chromosomes, Human / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D043864:DNA, Catenated / Q000378:metabolism*; D018105:DNA, Kinetoplast / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D008677:Metaphase; D008745:Methylation
D000951:Antigens, Neoplasm; D043864:DNA, Catenated; D018105:DNA, Kinetoplast; D004268:DNA-Binding Proteins; D011495:Histone-Lysine N-Methyltransferase; C510450:SETMAR protein, human; D004250:DNA Topoisomerases, Type II
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