title: The SET and transposase domain protein Metnase enhances chromosome decatenation: regulation by automethylation.
abstract: 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.
authors.affiliation: Division of Hematology-Oncology, Cancer Research and Treatment Center, Department of Medicine, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Williamson
authors.forename: Kanwaldeep Kaur
authors.initials: KK
authors.lastname: Rasila
authors.forename: Lori Kwan
authors.initials: LK
authors.lastname: Corwin
authors.forename: Justin
authors.initials: J
authors.lastname: Wray
authors.forename: Brian D
authors.initials: BD
authors.lastname: Beck
authors.forename: Virginia
authors.initials: V
authors.lastname: Severns
authors.forename: Charlotte
authors.initials: C
authors.lastname: Mobarak
authors.forename: Suk-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Jac A
authors.initials: JA
authors.lastname: Nickoloff
authors.forename: Robert
authors.initials: R
authors.lastname: Hromas
mesh_terms: 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
chemical_list: 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
references.citation: Mol Cell. 2007 Aug 17;27(4):596-608
references.pmid: 17707231
references.citation: Nat Rev Mol Cell Biol. 2002 Jun;3(6):430-40
references.pmid: 12042765
references.citation: Nature. 2006 Nov 30;444(7119):629-32
references.pmid: 17108971
references.citation: Biochemistry. 2007 Oct 9;46(40):11369-76
references.pmid: 17877369
references.citation: Br J Cancer. 2007 Jan 29;96(2):201-5
references.pmid: 17211475
references.citation: Nat Struct Mol Biol. 2005 Jul;12(7):589-93
references.pmid: 15965487
references.citation: Mol Cell Biol. 2007 Jun;27(12):4589-600
references.pmid: 17403897
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12044-9
references.pmid: 11593014
references.citation: Mol Biol Cell. 2006 May;17(5):2287-302
references.pmid: 16510521
references.citation: Cell Cycle. 2004 May;3(5):638-47
references.pmid: 15034300
references.citation: Mol Cell Biol. 1999 May;19(5):3551-60
references.pmid: 10207078
references.citation: Genes Dev. 2006 May 1;20(9):1162-74
references.pmid: 16651657
references.citation: Trends Genet. 1999 Aug;15(8):326-32
references.pmid: 10431195
references.citation: Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7809-13
references.pmid: 8395055
references.citation: Mol Cell. 2004 Sep 24;15(6):977-90
references.pmid: 15383286
references.citation: J Cell Biol. 2004 Aug 16;166(4):517-26
references.pmid: 15302851
references.citation: Nature. 1994 Dec 1;372(6505):467-70
references.pmid: 7984241
references.citation: Nucleic Acids Res. 1986 Jun 25;14(12):4837-48
references.pmid: 3088544
references.citation: Cell Cycle. 2006 Sep;5(17):1925-8
references.pmid: 16940751
references.citation: Eukaryot Cell. 2002 Aug;1(4):495-502
references.pmid: 12455998
references.citation: Cancer Res. 1991 Sep 15;51(18):4909-16
references.pmid: 1654205
references.citation: Mol Cell Biol. 2007 Feb;27(3):1125-32
references.pmid: 17130240
references.citation: J Biol Chem. 2008 Apr 4;283(14):9023-30
references.pmid: 18263876
references.citation: Cancer Res. 2004 Jul 15;64(14):4826-32
references.pmid: 15256452
references.citation: Cell Mol Life Sci. 2005 Mar;62(6):629-41
references.pmid: 15770416
references.citation: J Biol Chem. 2002 Sep 27;277(39):36832-8
references.pmid: 12147700
references.citation: Proc Natl Acad Sci U S A. 2006 May 23;103(21):8101-6
references.pmid: 16672366
references.citation: Nucleic Acids Res. 2007;35(21):7313-23
references.pmid: 17962312
references.citation: Hum Mol Genet. 2006 Apr 15;15 Spec No 1:R75-9
references.pmid: 16651372
references.citation: Nature. 2001 Feb 15;409(6822):860-921
references.pmid: 11237011
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18075-80
references.pmid: 16332963
references.citation: Genetica. 2007 Jun;130(2):105-20
references.pmid: 16912840
references.citation: Cell Cycle. 2004 May;3(5):627-8
references.pmid: 15107612
references.citation: J Natl Cancer Inst. 2003 Dec 17;95(24):1859-68
references.pmid: 14679155
references.citation: Nucleic Acids Res. 2007;35(15):5001-13
references.pmid: 17636313