title: TRF1 ensures the centromeric function of Aurora-B and proper chromosome segregation.
abstract: A cancer is a robustly evolving cell population originating from a normal diploid cell. Improper chromosome segregation causes aneuploidy, a driving force of cancer development and malignant progression. Telomeric repeat binding factor 1 (TRF1) has been established as a telomeric protein that negatively regulates telomere elongation by telomerase and promotes efficient DNA replication at telomeres. Intriguingly, overexpression of a mitotic kinase, Aurora-A, compromises efficient microtubule-kinetochore attachment in a TRF1-dependent manner. However, the precise role of TRF1 in mitosis remains elusive. Here we demonstrate that TRF1 is required for the centromeric function of Aurora-B, which ensures proper chromosome segregation. TRF1 depletion abolishes centromeric recruitment of Aurora-B and loosens sister centromere cohesion, resulting in the induction of merotelic kinetochore attachments, lagging chromosomes, and micronuclei. Accordingly, an absence of TRF1 in human and mouse diploid cells induces aneuploidy. These phenomena seem to be telomere independent, because a telomere-unbound TRF1 mutant can suppress the TRF1 knockdown phenotype. These observations indicate that TRF1 regulates the rigidity of the microtubule-kinetochore attachment, contributing to proper chromosome segregation and the maintenance of genomic integrity.
authors.affiliation: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Ohishi
authors.affiliation: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Muramatsu
authors.affiliation: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan hseimiya@jfcr.or.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Seimiya
mesh_terms: D000782:Aneuploidy; D000818:Animals; D064107:Aurora Kinase B / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002503:Centromere / Q000378:metabolism*; D020090:Chromosome Segregation; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000737:chemistry*; D051379:Mice; D008870:Microtubules / Q000737:chemistry*; D008938:Mitosis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D035321:Telomeric Repeat Binding Protein 1; D064107:Aurora Kinase B
references.citation: Cell. 2002 Feb 8;108(3):317-29
references.pmid: 11853667
references.citation: PLoS One. 2009 Aug 28;4(8):e6831
references.pmid: 19714251
references.citation: Nature. 1997 Feb 20;385(6618):740-3
references.pmid: 9034193
references.citation: Genes Dev. 2010 Jul 1;24(13):1364-76
references.pmid: 20551165
references.citation: Genes Dev. 2011 Sep 1;25(17):1807-19
references.pmid: 21865325
references.citation: Am J Pathol. 2002 Apr;160(4):1259-68
references.pmid: 11943711
references.citation: Genes Dev. 2009 Sep 1;23(17):2060-75
references.pmid: 19679647
references.citation: EMBO J. 2007 Nov 28;26(23):4867-78
references.pmid: 17962804
references.citation: Nature. 2008 Sep 11;455(7210):251-5
references.pmid: 18716626
references.citation: Oncogene. 2001 Mar 22;20(12):1497-508
references.pmid: 11313893
references.citation: J Biol Chem. 2002 Apr 19;277(16):14116-26
references.pmid: 11854288
references.citation: Mol Cell Biol. 1983 Apr;3(4):539-50
references.pmid: 6406835
references.citation: Dev Cell. 2006 Nov;11(5):741-50
references.pmid: 17084365
references.citation: Cancer Cell. 2005 Jan;7(1):25-37
references.pmid: 15652747
references.citation: Clin Cancer Res. 2006 Oct 1;12(19):5720-5
references.pmid: 17020976
references.citation: J Cell Biol. 2005 Oct 24;171(2):197-200
references.pmid: 16247021
references.citation: J Cell Sci. 2007 Apr 1;120(Pt 7):1245-55
references.pmid: 17356064
references.citation: PLoS One. 2009 Aug 10;4(8):e6564
references.pmid: 19668340
references.citation: Nature. 2009 Jul 9;460(7252):278-82
references.pmid: 19506557
references.citation: Nat Rev Cancer. 2005 Oct;5(10):773-85
references.pmid: 16195750
references.citation: Nat Commun. 2011 Jun 28;2:371
references.pmid: 21712819
references.citation: Mol Cell. 2002 Mar;9(3):515-25
references.pmid: 11931760
references.citation: Nat Rev Genet. 2012 Jan 24;13(3):189-203
references.pmid: 22269907
references.citation: EMBO J. 2012 May 2;31(9):2076-89
references.pmid: 22415365
references.citation: Nature. 2007 Nov 29;450(7170):745-9
references.pmid: 18046416
references.citation: Mol Cell. 2001 Aug;8(2):351-61
references.pmid: 11545737
references.citation: Genes Dev. 2005 Sep 15;19(18):2100-10
references.pmid: 16166375
references.citation: Anticancer Res. 2002 Mar-Apr;22(2B):1315-20
references.pmid: 12168944
references.citation: Mol Cell Biol. 2002 Jan;22(1):332-42
references.pmid: 11739745
references.citation: FEBS Lett. 2002 Mar 13;514(2-3):193-8
references.pmid: 11943150
references.citation: Curr Biol. 2006 Sep 5;16(17):1705-10
references.pmid: 16950107
references.citation: Cell. 2006 Mar 24;124(6):1283-98
references.pmid: 16564017
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):17974-8
references.pmid: 21997207
references.citation: Cell. 2009 Jul 10;138(1):90-103
references.pmid: 19596237
references.citation: Curr Biol. 2001 Oct 2;11(19):1512-6
references.pmid: 11591318
references.citation: Exp Ther Med. 2011 Jan;2(1):63-67
references.pmid: 22977470
references.citation: J Cell Biol. 2000 Nov 13;151(4):749-62
references.pmid: 11076961
references.citation: Exp Cell Res. 2008 Mar 10;314(5):1115-24
references.pmid: 18221737
references.citation: PLoS Biol. 2005 Mar;3(3):e86
references.pmid: 15737064
references.citation: Nat Genet. 2004 Jul;36(7):744-9
references.pmid: 15208629
references.citation: Curr Biol. 2006 Jul 11;16(13):1295-302
references.pmid: 16730176
references.citation: J Cell Biol. 2001 Apr 30;153(3):517-27
references.pmid: 11331303
references.citation: Cancer Res. 2010 Mar 1;70(5):2041-52
references.pmid: 20160025
references.citation: Cell. 2004 Sep 3;118(5):567-78
references.pmid: 15339662
references.citation: Dev Cell. 2003 Dec;5(6):853-64
references.pmid: 14667408
references.citation: Mol Biol Cell. 2004 Jul;15(7):3296-308
references.pmid: 15146063
references.citation: J Cell Biol. 2009 Oct 19;187(2):165-73
references.pmid: 19822671
references.citation: Mol Cell Biol. 2004 Mar;24(5):1944-55
references.pmid: 14966275
references.citation: J Cell Sci. 2002 Feb 1;115(Pt 3):507-15
references.pmid: 11861758
references.citation: Cell. 1998 Feb 6;92(3):401-13
references.pmid: 9476899
references.citation: J Biol Chem. 2004 Jan 9;279(2):1442-8
references.pmid: 14559908
references.citation: Nature. 2004 Feb 5;427(6974):510-7
references.pmid: 14730319
references.citation: EMBO J. 1998 Jun 1;17(11):3052-65
references.pmid: 9606188
references.citation: J Cell Sci. 2003 Oct 15;116(Pt 20):4213-25
references.pmid: 12953065
references.citation: J Cell Biol. 2008 Feb 25;180(4):665-72
references.pmid: 18283116
references.citation: Mol Cell Biol. 2009 Mar;29(6):1608-25
references.pmid: 19124610
references.citation: Mol Cell Biol. 2003 Sep;23(18):6533-41
references.pmid: 12944479
references.citation: Genes Dev. 2008 Nov 15;22(22):3089-114
references.pmid: 19056890
references.citation: Cell Cycle. 2013 Dec 1;12(23):3599-614
references.pmid: 24091727
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18012-7
references.pmid: 15604152