title: Aurora-B mediated ATM serine 1403 phosphorylation is required for mitotic ATM activation and the spindle checkpoint.
abstract: The ATM kinase plays a critical role in the maintenance of genetic stability. ATM is activated in response to DNA damage and is essential for cell-cycle checkpoints. Here, we report that ATM is activated in mitosis in the absence of DNA damage. We demonstrate that mitotic ATM activation is dependent on the Aurora-B kinase and that Aurora-B phosphorylates ATM on serine 1403. This phosphorylation event is required for mitotic ATM activation. Further, we show that loss of ATM function results in shortened mitotic timing and a defective spindle checkpoint, and that abrogation of ATM Ser1403 phosphorylation leads to this spindle checkpoint defect. We also demonstrate that mitotically activated ATM phosphorylates Bub1, a critical kinetochore protein, on Ser314. ATM-mediated Bub1 Ser314 phosphorylation is required for Bub1 activity and is essential for the activation of the spindle checkpoint. Collectively, our data highlight mechanisms of a critical function of ATM in mitosis.
authors.affiliation: Department of Radiation Oncology, The Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Yang
authors.forename: Xi
authors.initials: X
authors.lastname: Tang
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Guo
authors.forename: Yohei
authors.initials: Y
authors.lastname: Niikura
authors.forename: Katsumi
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Kemi
authors.initials: K
authors.lastname: Cui
authors.forename: Stephen T C
authors.initials: ST
authors.lastname: Wong
authors.forename: Li
authors.initials: L
authors.lastname: Fu
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D064107:Aurora Kinase B; D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005434:Flow Cytometry; D020868:Gene Silencing / Q000187:drug effects; D015894:Genome, Human; D042822:Genomic Instability; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000378:metabolism*; D008938:Mitosis / Q000235:genetics*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D012694:Serine; C576324:ATM protein, human; C576921:AURKB protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D064107:Aurora Kinase B; D064127:Aurora Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases
references.citation: Nat Struct Mol Biol. 2006 May;13(5):451-7
references.pmid: 16622404
references.citation: Nature. 2005 Mar 31;434(7033):605-11
references.pmid: 15758953
references.citation: Nat Cell Biol. 2010 May;12(5):492-9
references.pmid: 20364141
references.citation: Science. 2004 Apr 2;304(5667):93-6
references.pmid: 15064416
references.citation: Genes Dev. 2007 May 15;21(10):1163-8
references.pmid: 17504936
references.citation: Dev Cell. 2007 Feb;12(2):247-60
references.pmid: 17276342
references.citation: Nat Cell Biol. 2005 Jul;7(7):675-85
references.pmid: 15965469
references.citation: EMBO Rep. 2007 Jun;8(6):603-9
references.pmid: 17468739
references.citation: Genes Dev. 2010 Oct 1;24(19):2169-79
references.pmid: 20889715
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14244-8
references.pmid: 16179389
references.citation: Mol Biol Cell. 2005 Oct;16(10):5013-25
references.pmid: 16030261
references.citation: Curr Biol. 2009 Jul 14;19(13):1075-85
references.pmid: 19540122
references.citation: Cell Cycle. 2010 May 15;9(10):2027-36
references.pmid: 20458174
references.citation: Cell. 2001 Jan 26;104(2):247-57
references.pmid: 11207365
references.citation: Cell. 2006 Nov 3;127(3):539-52
references.pmid: 17081976
references.citation: J Cell Biochem. 2006 Dec 1;99(5):1267-74
references.pmid: 16775842
references.citation: Oncogene. 1997 Jul 10;15(2):159-67
references.pmid: 9244351
references.citation: Science. 2007 May 25;316(5828):1160-6
references.pmid: 17525332
references.citation: Dev Cell. 2007 Feb;12(2):167-8
references.pmid: 17276330
references.citation: Nature. 2004 Nov 18;432(7015):316-23
references.pmid: 15549093
references.citation: Cell. 2002 Oct 18;111(2):163-72
references.pmid: 12408861
references.citation: Mol Cancer Ther. 2006 Dec;5(12):2963-9
references.pmid: 17172401
references.citation: Nature. 2003 Jan 30;421(6922):499-506
references.pmid: 12556884
references.citation: J Cell Sci. 2002 Jan 1;115(Pt 1):71-9
references.pmid: 11801725
references.citation: Mol Cell Biol. 2008 Apr;28(8):2559-66
references.pmid: 18250156
references.citation: Science. 2005 Apr 22;308(5721):551-4
references.pmid: 15790808
references.citation: Cancer Res. 2002 Mar 15;62(6):1598-603
references.pmid: 11912127
references.citation: Cell. 2000 Jun 9;101(6):635-45
references.pmid: 10892650
references.citation: Nat Rev Cancer. 2003 Mar;3(3):155-68
references.pmid: 12612651
references.citation: Mol Pharmacol. 2007 Aug;72(2):320-6
references.pmid: 17507690
references.citation: Curr Opin Genet Dev. 2004 Feb;14(1):29-36
references.pmid: 15108802
references.citation: Curr Opin Cell Biol. 2005 Dec;17(6):583-9
references.pmid: 16226453
references.citation: Cell Cycle. 2008 May 1;7(9):1277-84
references.pmid: 18418045
references.citation: Cell Cycle. 2010 Dec 15;9(24):4805-11
references.pmid: 21150274
references.citation: Cancer Res. 1999 Jun 1;59(11):2602-7
references.pmid: 10363981
references.citation: Genes Dev. 2002 Mar 1;16(5):571-82
references.pmid: 11877377
references.citation: Genes Dev. 2002 Mar 1;16(5):560-70
references.pmid: 11877376
references.citation: Science. 2010 Jan 8;327(5962):172-7
references.pmid: 19965387
references.citation: EMBO J. 2006 Aug 9;25(15):3504-14
references.pmid: 16858402
references.citation: Nature. 2001 Jan 18;409(6818):355-9
references.pmid: 11201745
references.citation: Nat Rev Mol Cell Biol. 2008 Oct;9(10):759-69
references.pmid: 18813293
references.citation: Trends Cell Biol. 1996 Jun;6(6):228-34
references.pmid: 15157461
references.citation: Nature. 2000 Apr 6;404(6778):613-7
references.pmid: 10766245
references.citation: J Cell Biol. 2007 Oct 22;179(2):255-67
references.pmid: 17938250
references.citation: Cancer Res. 2005 Oct 1;65(19):8747-53
references.pmid: 16204044
references.citation: Curr Biol. 2005 Apr 26;15(8):778-86
references.pmid: 15854913
references.citation: Cancer Res. 1998 Nov 1;58(21):4923-9
references.pmid: 9810001
references.citation: Sci Signal. 2010 Jun 01;3(124):ra44
references.pmid: 20516478
references.citation: Oncogene. 2007 Dec 10;26(56):7741-8
references.pmid: 18066086
references.citation: Hum Mol Genet. 2009 Jul 15;18(14):2656-69
references.pmid: 19414482
references.citation: J Cell Biol. 2010 Jul 26;190(2):197-207
references.pmid: 20660628
references.citation: Curr Biol. 2005 May 24;15(10):R379-82
references.pmid: 15916939