title: Regulation of repair choice: Cdk1 suppresses recruitment of end joining factors at DNA breaks.
abstract: Cell cycle plays a crucial role in regulating the pathway used to repair DNA double-strand breaks (DSBs). In Saccharomyces cerevisiae, homologous recombination is primarily limited to non-G(1) cells as the formation of recombinogenic single-stranded DNA requires CDK1-dependent 5' to 3' resection of DNA ends. However, the effect of cell cycle on non-homologous end joining (NHEJ) is not yet clearly defined. Using an assay to quantitatively measure the contributions of each repair pathway to repair product formation and cellular survival after DSB induction, we found that NHEJ is most efficient at G(1), and markedly repressed at G(2). Repression of NHEJ at G(2) is achieved by efficient end resection and by the reduced association of core NHEJ proteins with DNA breaks, both of which depend on the CDK1 activity. Importantly, repression of 5' end resection by CDK1 inhibition at G(2) alone did not fully restore either physical association of Ku/Dnl4-Lif1 with DSBs or NHEJ proficiency to the level at G(1). Expression of excess Ku can partially offset the inhibition of end joining at G(2). The results suggest that regulation of Ku/Dnl4-Lif1 affinity for DNA ends may contribute to the cell cycle-dependent modulation of NHEJ efficiency.
authors.affiliation: Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 78245, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Eun Yong
authors.initials: EY
authors.lastname: Shim
authors.forename: Melody
authors.initials: M
authors.lastname: Davis
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Lee
mesh_terms: D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle; D002470:Cell Survival; D053903:DNA Breaks, Double-Stranded; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000201:enzymology* / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C114091:LIF1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C081647:high affinity DNA-binding factor, S cerevisiae; D016203:CDC2 Protein Kinase; D011088:DNA Ligases; D045643:DNA Repair Enzymes; D000072481:DNA Ligase ATP
references.citation: Cell Res. 2008 Jan;18(1):134-47
references.pmid: 18157161
references.citation: DNA Repair (Amst). 2006 Sep 8;5(9-10):1030-41
references.pmid: 16934538
references.citation: Genes Dev. 2004 Sep 15;18(18):2249-54
references.pmid: 15371339
references.citation: Nature. 2001 Aug 9;412(6847):607-14
references.pmid: 11493912
references.citation: Annu Rev Genet. 2004;38:233-71
references.pmid: 15568977
references.citation: Mol Cell Biol. 1995 Feb;15(2):883-91
references.pmid: 7823954
references.citation: Genetics. 2002 Jul;161(3):1015-27
references.pmid: 12136007
references.citation: Nature. 2004 Oct 21;431(7011):1011-7
references.pmid: 15496928
references.citation: Curr Top Dev Biol. 2001;52:1-53
references.pmid: 11529427
references.citation: Genetics. 2008 Dec;180(4):1809-19
references.pmid: 18832348
references.citation: Genes Dev. 2008 Feb 15;22(4):411-5
references.pmid: 18281457
references.citation: Mol Cell Biol. 2003 Aug;23(16):5706-15
references.pmid: 12897142
references.citation: Mutat Res. 1997 Sep;384(3):205-11
references.pmid: 9330616
references.citation: DNA Repair (Amst). 2006 Sep 8;5(9-10):1021-9
references.pmid: 16807135
references.citation: Annu Rev Genet. 2005;39:431-51
references.pmid: 16285867
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4777-82
references.pmid: 15738391
references.citation: Mol Cell Biol. 1999 Nov;19(11):7681-7
references.pmid: 10523656
references.citation: Microbiol Mol Biol Rev. 1999 Jun;63(2):349-404
references.pmid: 10357855
references.citation: Annu Rev Genet. 2006;40:363-83
references.pmid: 16895466
references.citation: Cell. 2004 Apr 16;117(2):171-84
references.pmid: 15084256
references.citation: Nature. 2009 May 21;459(7245):460-3
references.pmid: 19357644
references.citation: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):817-26
references.pmid: 15279766
references.citation: Mol Cell Biol. 2004 Oct;24(20):8917-28
references.pmid: 15456866
references.citation: Genetics. 2001 Feb;157(2):579-89
references.pmid: 11156980
references.citation: Mol Cell Biol. 2005 Feb;25(3):896-906
references.pmid: 15657419
references.citation: Nature. 2001 Dec 6;414(6864):666-9
references.pmid: 11740566
references.citation: Mol Cell Biol. 2004 May;24(10):4151-65
references.pmid: 15121837
references.citation: EMBO J. 2004 Dec 8;23(24):4868-75
references.pmid: 15549137
references.citation: EMBO J. 1998 Sep 15;17(18):5497-508
references.pmid: 9736627
references.citation: Mol Cell Biol. 1997 Mar;17(3):1425-33
references.pmid: 9032269
references.citation: Genes Dev. 2001 Dec 15;15(24):3237-42
references.pmid: 11751629
references.citation: Genetics. 2008 Oct;180(2):771-83
references.pmid: 18716325
references.citation: DNA Repair (Amst). 2005 Jul 12;4(7):782-92
references.pmid: 15951249
references.citation: Mol Cell. 2007 Oct 12;28(1):134-46
references.pmid: 17936710
references.citation: Science. 2002 Jul 26;297(5581):552-7
references.pmid: 12142524
references.citation: Cell. 2004 Sep 17;118(6):699-713
references.pmid: 15369670
references.citation: Mol Cell Biol. 2005 May;25(10):3934-44
references.pmid: 15870268
references.citation: DNA Repair (Amst). 2006 Sep 8;5(9-10):998-1009
references.pmid: 16807137
references.citation: Mol Cell. 2002 Nov;10(5):1189-99
references.pmid: 12453425
references.citation: Nat Struct Mol Biol. 2007 Jul;14(7):639-46
references.pmid: 17589524
references.citation: Nature. 2008 Oct 2;455(7213):689-92
references.pmid: 18716619
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10077-82
references.pmid: 10963670
references.citation: Curr Biol. 2000 Feb 10;10(3):165-8
references.pmid: 10679327
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3758-63
references.pmid: 11904432
references.citation: EMBO Rep. 2008 Aug;9(8):810-8
references.pmid: 18600234