title: KDM4C (GASC1) lysine demethylase is associated with mitotic chromatin and regulates chromosome segregation during mitosis.
abstract: Various types of human cancers exhibit amplification or deletion of KDM4A-D members, which selectively demethylate H3K9 and H3K36, thus implicating their activity in promoting carcinogenesis. On this basis, it was hypothesized that dysregulated expression of KDM4A-D family promotes chromosomal instabilities by largely unknown mechanisms. Here, we show that unlike KDM4A-B, KDM4C is associated with chromatin during mitosis. This association is accompanied by a decrease in the mitotic levels of H3K9me3. We also show that the C-terminal region, containing the Tudor domains of KDM4C, is essential for its association with mitotic chromatin. More specifically, we show that R919 residue on the proximal Tudor domain of KDM4C is critical for its association with chromatin during mitosis. Interestingly, we demonstrate that depletion or overexpression of KDM4C, but not KDM4B, leads to over 3-fold increase in the frequency of abnormal mitotic cells showing either misaligned chromosomes at metaphase, anaphase-telophase lagging chromosomes or anaphase-telophase bridges. Furthermore, overexpression of KDM4C demethylase-dead mutant has no detectable effect on mitotic chromosome segregation. Altogether, our findings implicate KDM4C demethylase activity in regulating the fidelity of mitotic chromosome segregation by a yet unknown mechanism.
authors.affiliation: Department of Biology, Technion, Israel Institute of Technology, Haifa 3200003, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Kupershmit
authors.affiliation: Department of Biology, Technion, Israel Institute of Technology, Haifa 3200003, Israel.
authors.forename: Hanan
authors.initials: H
authors.lastname: Khoury-Haddad
authors.affiliation: Department of Biology, Technion, Israel Institute of Technology, Haifa 3200003, Israel.
authors.forename: Samah W
authors.initials: SW
authors.lastname: Awwad
authors.affiliation: Department of Biology, Technion, Israel Institute of Technology, Haifa 3200003, Israel.
authors.forename: Noga
authors.initials: N
authors.lastname: Guttmann-Raviv
authors.affiliation: Department of Biology, Technion, Israel Institute of Technology, Haifa 3200003, Israel ayoubn@technion.ac.il.
authors.forename: Nabieh
authors.initials: N
authors.lastname: Ayoub
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000201:enzymology*; D020090:Chromosome Segregation; D056484:Jumonji Domain-Containing Histone Demethylases / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D008938:Mitosis / Q000235:genetics*; D017434:Protein Structure, Tertiary
chemical_list: D002843:Chromatin; C413655:KDM4C protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human; C494424:KDM4A protein, human
references.citation: Nature. 2005 Dec 22;438(7071):1116-22
references.pmid: 16222246
references.citation: Trends Mol Med. 2007 Sep;13(9):373-80
references.pmid: 17822959
references.citation: Development. 2012 Jul;139(13):2255-66
references.pmid: 22669818
references.citation: Cancer Res. 2000 Sep 1;60(17):4735-9
references.pmid: 10987278
references.citation: PLoS One. 2012;7(4):e34618
references.pmid: 22514644
references.citation: Nat Struct Mol Biol. 2013 Mar;20(3):259-66
references.pmid: 23463310
references.citation: Cell. 2007 Feb 23;128(4):707-19
references.pmid: 17320508
references.citation: Cell Res. 2011 Apr;21(4):564-78
references.pmid: 21423274
references.citation: Oncogene. 2012 Jul 5;31(27):3244-53
references.pmid: 22081068
references.citation: Cell. 2013 Aug 1;154(3):541-55
references.pmid: 23871696
references.citation: Cell. 2005 Apr 22;121(2):167-78
references.pmid: 15851025
references.citation: Cell. 2007 Feb 23;128(4):693-705
references.pmid: 17320507
references.citation: Mol Cell Biol. 2005 Aug;25(15):6404-14
references.pmid: 16024779
references.citation: Oncogene. 2009 Dec 17;28(50):4491-500
references.pmid: 19784073
references.citation: Nature. 2006 Feb 16;439(7078):811-6
references.pmid: 16362057
references.citation: Cell. 2009 Oct 2;139(1):123-34
references.pmid: 19804758
references.citation: BMC Cancer. 2012 Nov 14;12:516
references.pmid: 23148692
references.citation: Cell. 2008 Oct 17;135(2):272-83
references.pmid: 18957202
references.citation: Nat Cell Biol. 2010 Jul;12(7):719-27
references.pmid: 20562864
references.citation: Nat Rev Genet. 2012 Apr 03;13(5):343-57
references.pmid: 22473383
references.citation: J Biol Chem. 2013 Jul 19;288(29):21376-21388
references.pmid: 23744078
references.citation: Nat Genet. 2005 Apr;37(4):391-400
references.pmid: 15765097
references.citation: Biochem Biophys Res Commun. 2007 Aug 3;359(3):742-6
references.pmid: 17555712
references.citation: Essays Biochem. 2010 Sep 20;48(1):75-87
references.pmid: 20822487
references.citation: Cell. 2006 May 5;125(3):467-81
references.pmid: 16603238
references.citation: Nature. 1997 Sep 25;389(6649):349-52
references.pmid: 9311776
references.citation: Cell. 2002 Feb 22;108(4):489-500
references.pmid: 11909520
references.citation: Biochem Biophys Res Commun. 2007 Feb 23;353(4):973-7
references.pmid: 17207460
references.citation: Mol Cell. 2012 Nov 30;48(4):491-507
references.pmid: 23200123
references.citation: Trends Cell Biol. 2010 Nov;20(11):662-71
references.pmid: 20863703
references.citation: Cell. 2004 Dec 29;119(7):941-53
references.pmid: 15620353
references.citation: Nucleic Acids Res. 2013 Aug;41(14):6892-904
references.pmid: 23723241
references.citation: Trends Mol Med. 2004 Oct;10(10):500-7
references.pmid: 15464450
references.citation: Cancer Res. 2013 May 15;73(10):2936-42
references.pmid: 23644528
references.citation: Cell. 2006 Dec 29;127(7):1361-73
references.pmid: 17190600
references.citation: Nat Struct Mol Biol. 2010 Jan;17(1):38-43
references.pmid: 20023638
references.citation: Am J Transl Res. 2013 Dec 01;6(1):1-15
references.pmid: 24349617
references.citation: J Biol Chem. 2011 Dec 2;286(48):41616-41625
references.pmid: 21914792
references.citation: Genes Dev. 2010 Apr 1;24(7):636-46
references.pmid: 20360382
references.citation: Nat Rev Genet. 2006 Sep;7(9):715-27
references.pmid: 16983801
references.citation: Cell Res. 2010 Feb;20(2):166-73
references.pmid: 20101266
references.citation: Nat Struct Mol Biol. 2008 Jan;15(1):109-11
references.pmid: 18084306
references.citation: J Biol Chem. 2006 Mar 31;281(13):8888-97
references.pmid: 16373353
references.citation: Gene. 2010 Jan 15;450(1-2):8-17
references.pmid: 19786080
references.citation: Genes Dev. 2006 Jun 15;20(12):1557-62
references.pmid: 16738407
references.citation: Acta Biochim Biophys Sin (Shanghai). 2012 Jan;44(1):14-27
references.pmid: 22194010
references.citation: Nature. 2002 Oct 10;419(6907):624-9
references.pmid: 12374981
references.citation: Trends Biochem Sci. 2002 Aug;27(8):396-402
references.pmid: 12151224
references.citation: Cell. 2013 Feb 14;152(4):685-9
references.pmid: 23375745
references.citation: Nat Genet. 2009 Apr;41(4):465-72
references.pmid: 19270706
references.citation: J Biol Chem. 2010 Oct 8;285(41):31370-9
references.pmid: 20675387
references.citation: Development. 2013 Jun;140(12):2513-24
references.pmid: 23715545
references.citation: Nature. 2006 Jul 20;442(7100):307-11
references.pmid: 16732293
references.citation: Proc Natl Acad Sci U S A. 2012 Dec 4;109(49):E3367-76
references.pmid: 23129632
references.citation: Cell. 2006 May 19;125(4):691-702
references.pmid: 16677698
references.citation: Cell Rep. 2012 Nov 29;2(5):1233-43
references.pmid: 23168260
references.citation: Dev Cell. 2005 Dec;9(6):769-79
references.pmid: 16326389
references.citation: Curr Biol. 2002 Jun 4;12(11):900-5
references.pmid: 12062053
references.citation: Cell. 2003 Apr 4;113(1):127-37
references.pmid: 12679040
references.citation: Nat Rev Genet. 2010 Apr;11(4):285-96
references.pmid: 20300089
references.citation: Cell. 2001 Nov 2;107(3):323-37
references.pmid: 11701123
references.citation: Nat Cell Biol. 2007 Mar;9(3):347-53
references.pmid: 17277772
references.citation: Mol Cell. 2010 Dec 10;40(5):736-48
references.pmid: 21145482
references.citation: J Cell Biol. 1998 Jun 1;141(5):1207-15
references.pmid: 9606212
references.citation: Nature. 2004 Nov 18;432(7015):406-11
references.pmid: 15525939
references.citation: Hum Mol Genet. 2008 Oct 1;17(19):3055-74
references.pmid: 18632687
references.citation: Nat Rev Mol Cell Biol. 2013 Apr;14(4):211-24
references.pmid: 23847782
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):E728-37
references.pmid: 24550317
references.citation: Genes Dev. 2007 Oct 15;21(20):2545-57
references.pmid: 17938240
references.citation: Curr Biol. 2010 Aug 24;20(16):R666-7
references.pmid: 20728048
references.citation: Nature. 2006 Jul 20;442(7100):312-6
references.pmid: 16732292
references.citation: Mol Biol Rep. 2008 Dec;35(4):551-6
references.pmid: 17668288
references.citation: Mol Cell. 2007 Jan 12;25(1):1-14
references.pmid: 17218267
references.citation: J Biol Chem. 2013 May 24;288(21):14681-7
references.pmid: 23589305
references.citation: J Pathol. 2006 Mar;208(4):554-63
references.pmid: 16400626
references.citation: PLoS One. 2011 Mar 18;6(3):e17830
references.pmid: 21445275
references.citation: Nucleic Acids Res. 2013 Apr;41(8):4433-46
references.pmid: 23435229
references.citation: Nature. 2007 May 24;447(7143):407-12
references.pmid: 17522673
references.citation: Chromosoma. 1999 Aug;108(4):220-34
references.pmid: 10460410
references.citation: Proc Natl Acad Sci U S A. 2011 May 3;108(18):7541-6
references.pmid: 21502505
references.citation: Science. 2003 Jan 31;299(5607):721-5
references.pmid: 12560555
references.citation: Biochem Biophys Res Commun. 2011 Dec 16;416(3-4):372-8
references.pmid: 22133676
references.citation: EMBO J. 2012 Apr 18;31(8):1865-78
references.pmid: 22373579
references.citation: Genes Dev. 2004 Jun 1;18(11):1251-62
references.pmid: 15145825
references.citation: PLoS Comput Biol. 2005 Nov;1(6):e66
references.pmid: 16322766
references.citation: Biochim Biophys Acta. 2002 Oct 2;1603(1):19-29
references.pmid: 12242108
references.citation: Science. 2006 May 5;312(5774):748-51
references.pmid: 16601153
references.citation: Nat Rev Mol Cell Biol. 2005 Nov;6(11):838-49
references.pmid: 16261189
references.citation: Br J Cancer. 2007;96 Suppl:R31-9
references.pmid: 17393583
references.citation: Curr Biol. 2005 May 24;15(10):R379-82
references.pmid: 15916939
references.citation: Nat Rev Mol Cell Biol. 2011 Sep 14;12(10):629-42
references.pmid: 21915143