title: ATM-mediated Mad1 Serine 214 phosphorylation regulates Mad1 dimerization and the spindle assembly checkpoint.
abstract: The spindle assembly checkpoint (SAC), which blocks anaphase onset until all chromosomes have bi-oriented, is one of the key self-monitoring systems of the eukaryotic cell cycle for genome stability. The mitotic arrest-deficient protein 1 (Mad1), a critical component of the SAC, is hyperphosphorylated in mitosis. However, the kinases responsible for Mad1 phosphorylation and its functional significance are not fully understood. Here we report that Mad1 is phosphorylated on Serine 214 by the Ataxia-Telangiectasia Mutated (ATM) kinase, a critical DNA damage response protein also activated in mitosis and required for the SAC. We demonstrate that Mad1 Serine 214 phosphorylation promotes the formation of homodimerization of Mad1 and its heterodimerization with Mad2. Further we show that Mad1 Serine 214 phosphorylation contribute to activation of the SAC and the maintenance of chromosomal stability. Together, these findings reveal an important role of ATM-mediated Mad1 Serine 214 phosphorylation in mitosis.
authors.affiliation: Department of Radiation Oncology, Houston Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Oncology, Drug Discovery Division, Southern Research Institute, Birmingham, AL 35205, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, Houston Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Radiation Oncology, Houston Methodist Hospital Research Institute, Houston, TX 77030, USA, Laboratory of Radiobiology, Jilin University School of Public Health, Changchun 130001, China.
authors.forename: Dejuan
authors.initials: D
authors.lastname: Kong
authors.affiliation: Department of Oncology, Drug Discovery Division, Southern Research Institute, Birmingham, AL 35205, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Medicinal Chemistry, Southern Research Institute, Birmingham, AL 35205, USA and.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Houston Methodist Hospital Research Institute, Houston, TX 77030, USA.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Houston Methodist Hospital Research Institute, Houston, TX 77030, USA.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Laboratory of Radiobiology, Jilin University School of Public Health, Changchun 130001, China.
authors.forename: Shumei
authors.initials: S
authors.lastname: Ma
authors.affiliation: Laboratory of Radiobiology, Jilin University School of Public Health, Changchun 130001, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: Peiyu
authors.initials: P
authors.lastname: Pu
authors.affiliation: Department of Radiation Oncology, Houston Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Oncology, Drug Discovery Division, Southern Research Institute, Birmingham, AL 35205, USA, Cancer Cell Biology Program, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35205, USA xu@sri.org.
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D064246:Mad2 Proteins / Q000378:metabolism; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D009687:Nuclear Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases
references.citation: Biochim Biophys Acta. 2008 Dec;1783(12):2223-33
references.pmid: 18804494
references.citation: Biol Reprod. 2008 Oct;79(4):718-26
references.pmid: 18596218
references.citation: Nat Cell Biol. 2010 May;12(5):492-9
references.pmid: 20364141
references.citation: Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6549-54
references.pmid: 22493223
references.citation: Cell. 1998 Apr 3;93(1):81-91
references.pmid: 9546394
references.citation: Oncogene. 2006 Apr 6;25(15):2137-47
references.pmid: 16288203
references.citation: Curr Opin Genet Dev. 1999 Feb;9(1):69-75
references.pmid: 10072359
references.citation: Cell. 2005 Mar 25;120(6):739-46
references.pmid: 15797376
references.citation: Curr Biol. 2000 Jun 1;10(11):675-8
references.pmid: 10837255
references.citation: Science. 2007 May 25;316(5828):1160-6
references.pmid: 17525332
references.citation: Biomed J. 2014 Jan-Feb;37(1):3-9
references.pmid: 24667671
references.citation: J Biol Chem. 2008 Dec 19;283(51):35834-44
references.pmid: 18922800
references.citation: Dev Cell. 2007 Feb;12(2):247-60
references.pmid: 17276342
references.citation: Curr Opin Genet Dev. 2000 Feb;10(1):26-31
references.pmid: 10679385
references.citation: Cancer Res. 2000 Mar 15;60(6):1531-5
references.pmid: 10749118
references.citation: DNA Repair (Amst). 2012 Feb 1;11(2):185-91
references.pmid: 22071147
references.citation: Cancer Res. 2007 Jan 1;67(1):160-6
references.pmid: 17210695
references.citation: Mol Cell. 2011 Nov 18;44(4):597-608
references.pmid: 22099307
references.citation: Mol Cancer Res. 2008 Apr;6(4):517-24
references.pmid: 18403632
references.citation: Oncogene. 2004 Mar 15;23(11):2016-27
references.pmid: 15021889
references.citation: Nat Cell Biol. 2011 Apr;13(4):475-82
references.pmid: 21394085
references.citation: Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):E2205-14
references.pmid: 22778409