title: The MCM8-MCM9 complex promotes RAD51 recruitment at DNA damage sites to facilitate homologous recombination.
abstract: The minichromosome maintenance protein homologs MCM8 and MCM9 have previously been implicated in DNA replication elongation and prereplication complex (pre-RC) formation, respectively. We found that MCM8 and MCM9 physically associate with each other and that MCM8 is required for the stability of MCM9 protein in mammalian cells. Depletion of MCM8 or MCM9 in human cancer cells or the loss of function MCM9 mutation in mouse embryo fibroblasts sensitizes cells to the DNA interstrand cross-linking (ICL) agent cisplatin. Consistent with a role in the repair of ICLs by homologous recombination (HR), knockdown of MCM8 or MCM9 significantly reduces HR repair efficiency. Chromatin immunoprecipitation analysis using human DR-GFP cells or Xenopus egg extract demonstrated that MCM8 and MCM9 proteins are rapidly recruited to DNA damage sites and promote RAD51 recruitment. Thus, these two metazoan-specific MCM homologs are new components of HR and may represent novel targets for treating cancer in combination with DNA cross-linking agents.
authors: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA.
authors: Jonghoon
authors: J
authors: Park
authors: David T
authors: DT
authors: Long
authors: Kyung Yong
authors: KY
authors: Lee
authors: Tarek
authors: T
authors: Abbas
authors: Etsuko
authors: E
authors: Shibata
authors: Masamitsu
authors: M
authors: Negishi
authors: Yunhai
authors: Y
authors: Luo
authors: John C
authors: JC
authors: Schimenti
authors: Agnieszka
authors: A
authors: Gambus
authors: Johannes C
authors: JC
authors: Walter
authors: Anindya
authors: A
authors: Dutta
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D057809:HEK293 Cells; D006367:HeLa Cells; D059765:Homologous Recombination; D006801:Humans; D051379:Mice; D064110:Minichromosome Maintenance Proteins; D034622:RNA Interference; D034741:RNA, Small Interfering; D051135:Rad51 Recombinase / Q000378:metabolism*; D059767:Recombinational DNA Repair; D014981:Xenopus
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C471623:MCM8 protein, human; C501931:MCM9 protein, human; D064110:Minichromosome Maintenance Proteins; D002945:Cisplatin
references: Cancer Res. 2010 Feb 1;70(3):988-95
references: 20103620
references: Mol Cell. 2012 Jan 13;45(1):75-86
references: 22153967
references: Mol Cell. 2012 Aug 24;47(4):511-22
references: 22771115
references: Genes Dev. 1999 Oct 15;13(20):2633-8
references: 10541549
references: EMBO J. 2006 Oct 18;25(20):4921-32
references: 17036055
references: Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17702-7
references: 21987787
references: Mol Cell Biol. 2005 Feb;25(4):1560-8
references: 15684404
references: Annu Rev Genet. 2010;44:113-39
references: 20690856
references: Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):16906-11
references: 18971343
references: Oncogene. 2001 Sep 27;20(43):6233-40
references: 11593432
references: Science. 2011 Jul 1;333(6038):84-7
references: 21719678
references: Cell. 2009 Mar 20;136(6):1032-43
references: 19303847
references: Gene. 2005 Dec 5;362:51-6
references: 16226853
references: BMC Evol Biol. 2009 Mar 17;9:60
references: 19292915
references: Mol Cell Biol. 2010 Feb;30(4):1088-96
references: 19995904
references: Cell. 2010 Jul 9;142(1):77-88
references: 20603016
references: Annu Rev Genet. 2011;45:247-71
references: 21910633
references: Microbiol Mol Biol Rev. 2009 Dec;73(4):652-83
references: 19946136
references: Science. 2009 Dec 18;326(5960):1698-701
references: 19965384
references: Nucleic Acids Res. 2003 Jun 1;31(11):2915-25
references: 12771218
references: Annu Rev Biochem. 2008;77:229-57
references: 18275380
references: Nucleic Acids Res. 2003 Jan 15;31(2):570-9
references: 12527764
references: Mol Cell. 2012 Aug 24;47(4):523-34
references: 22771120
references: J Biol Chem. 2012 Apr 6;287(15):11891-8
references: 22334659
references: Cell. 2009 Jul 10;138(1):63-77
references: 19596235
references: PLoS One. 2010 Aug 24;5(8):e12373
references: 20808772
references: Nature. 2007 Nov 22;450(7169):509-14
references: 17965729
references: Trends Biochem Sci. 2009 May;34(5):264-72
references: 19375328
references: PLoS Genet. 2005 Sep;1(3):e40
references: 16189551
references: Nat Genet. 2009 Jun;41(6):724-8
references: 19448621
references: Hum Mol Genet. 2011 Jan 1;20(1):186-92
references: 20952801
references: Mol Cell. 2008 Jul 25;31(2):190-200
references: 18657502
references: Mol Cell. 2010 Jul 9;39(1):36-47
references: 20603073
references: Cell. 2010 Jul 9;142(1):65-76
references: 20603015
references: Genes Dev. 2008 Oct 15;22(20):2767-72
references: 18923075
references: Cell. 2009 Oct 2;139(1):87-99
references: 19804755
references: PLoS One. 2007 Sep 05;2(9):e833
references: 17786205
references: Mol Cell. 1998 Mar;1(4):519-29
references: 9660936
references: PLoS Genet. 2010 Sep 09;6(9):e1001110
references: 20838603
references: Nat Cell Biol. 2006 Jan;8(1):91-9
references: 16341205
references: J Biol Chem. 2010 May 21;285(21):15739-45
references: 20348101
references: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8193-8
references: 12826610
references: Cell. 2005 Feb 11;120(3):315-28
references: 15707891
references: Nat Rev Cancer. 2011 Jun 24;11(7):467-80
references: 21701511
references: Annu Rev Biochem. 2008;77:259-87
references: 18518821
references: Biochem Biophys Res Commun. 2005 Jun 3;331(2):669-74
references: 15850810
references: Cell. 2008 Sep 19;134(6):969-80
references: 18805090
references: Chembiochem. 2005 Jan;6(1):27-32
references: 15637664