title: Phosphorylation: the molecular switch of double-strand break repair.
abstract: Repair of double-stranded breaks (DSBs) is vital to maintaining genomic stability. In mammalian cells, DSBs are resolved in one of the following complex repair pathways: nonhomologous end-joining (NHEJ), homologous recombination (HR), or the inclusive DNA damage response (DDR). These repair pathways rely on factors that utilize reversible phosphorylation of proteins as molecular switches to regulate DNA repair. Many of these molecular switches overlap and play key roles in multiple pathways. For example, the NHEJ pathway and the DDR both utilize DNA-PK phosphorylation, whereas the HR pathway mediates repair with phosphorylation of RPA2, BRCA1, and BRCA2. Also, the DDR pathway utilizes the kinases ATM and ATR, as well as the phosphorylation of H2AX and MDC1. Together, these molecular switches regulate repair of DSBs by aiding in DSB recognition, pathway initiation, recruitment of repair factors, and the maintenance of repair mechanisms.
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Summers
authors.forename: F
authors.initials: F
authors.lastname: Shen
authors.forename: E A
authors.initials: EA
authors.lastname: Sierra Potchanant
authors.forename: E A
authors.initials: EA
authors.lastname: Phipps
authors.forename: R J
authors.initials: RJ
authors.lastname: Hickey
authors.forename: L H
authors.initials: LH
authors.lastname: Malkas
references.citation: Environ Mol Mutagen. 2010 Oct-Dec;51(8-9):879-89
references.pmid: 20818630
references.citation: DNA Repair (Amst). 2010 Dec 10;9(12):1307-14
references.pmid: 21030321
references.citation: J Biol Chem. 2000 Aug 25;275(34):26196-205
references.pmid: 10854421
references.citation: Mol Cell Biol. 2005 Dec;25(24):10842-52
references.pmid: 16314509
references.citation: EMBO J. 2006 Aug 9;25(15):3504-14
references.pmid: 16858402
references.citation: Mutat Res. 1995 Mar;336(2):101-13
references.pmid: 7885381
references.citation: Cell Res. 2008 Jan;18(1):134-47
references.pmid: 18157161
references.citation: Mol Cell. 2001 Feb;7(2):273-82
references.pmid: 11239456
references.citation: Nat Rev Mol Cell Biol. 2010 Mar;11(3):196-207
references.pmid: 20177395
references.citation: Curr Opin Cell Biol. 2009 Apr;21(2):245-55
references.pmid: 19230643
references.citation: Nucleic Acids Res. 2006 Feb 18;34(4):1112-20
references.pmid: 16488883
references.citation: J Biol Chem. 2004 Sep 3;279(36):37282-90
references.pmid: 15194694
references.citation: Nat Rev Mol Cell Biol. 2008 Aug;9(8):616-27
references.pmid: 18594563
references.citation: Genes Dev. 2000 Jan 1;14(1):1-10
references.pmid: 10640269
references.citation: Nature. 2005 Mar 31;434(7033):598-604
references.pmid: 15800615
references.citation: DNA Repair (Amst). 2003 Nov 21;2(11):1239-52
references.pmid: 14599745
references.citation: Nucleic Acids Res. 2007;35(12):3869-78
references.pmid: 17526517
references.citation: EMBO J. 2006 Aug 23;25(16):3880-9
references.pmid: 16874298
references.citation: J Biol Chem. 2011 Mar 18;286(11):9107-19
references.pmid: 21149446
references.citation: Nature. 2005 Mar 31;434(7033):605-11
references.pmid: 15758953
references.citation: Cell. 1997 Jan 24;88(2):265-75
references.pmid: 9008167
references.citation: J Biol Chem. 2001 Oct 12;276(41):38242-8
references.pmid: 11477099
references.citation: Mol Cell Biol. 2007 May;27(10):3881-90
references.pmid: 17353268
references.citation: Mol Cell. 2001 Feb;7(2):263-72
references.pmid: 11239455
references.citation: Crit Rev Biochem Mol Biol. 1999;34(3):141-80
references.pmid: 10473346
references.citation: Science. 2003 Jun 6;300(5625):1542-8
references.pmid: 12791985
references.citation: Biochemistry. 1999 Feb 9;38(6):1819-28
references.pmid: 10026262
references.citation: Cell Cycle. 2003 Sep-Oct;2(5):426-7
references.pmid: 12963833
references.citation: Nature. 2003 Jan 30;421(6922):499-506
references.pmid: 12556884
references.citation: Mol Cell Biol. 2004 Mar;24(5):1930-43
references.pmid: 14966274
references.citation: J Biol Chem. 1997 Sep 19;272(38):23896-904
references.pmid: 9295339
references.citation: Nat Cell Biol. 2006 Jan;8(1):37-45
references.pmid: 16327781
references.citation: Trends Cell Biol. 2009 May;19(5):207-17
references.pmid: 19342239
references.citation: Adv Immunol. 2008;99:33-58
references.pmid: 19117531
references.citation: Cancer Sci. 2004 Nov;95(11):866-71
references.pmid: 15546503
references.citation: DNA Repair (Amst). 2004 Mar 4;3(3):267-76
references.pmid: 15177042
references.citation: EMBO J. 2009 Oct 21;28(20):3067-73
references.pmid: 19779456
references.citation: Science. 2002 May 3;296(5569):922-7
references.pmid: 11934988
references.citation: J Mol Biol. 2009 Jan 23;385(3):800-10
references.pmid: 19071136
references.citation: J Mol Biol. 2003 Feb 7;326(1):93-103
references.pmid: 12547193
references.citation: Nature. 2009 Oct 22;461(7267):1071-8
references.pmid: 19847258
references.citation: Cell. 2005 Dec 29;123(7):1213-26
references.pmid: 16377563
references.citation: EMBO Rep. 2007 Jan;8(1):56-62
references.pmid: 17159921
references.citation: Annu Rev Genet. 2004;38:233-71
references.pmid: 15568977
references.citation: Annu Rev Biochem. 1997;66:61-92
references.pmid: 9242902
references.citation: Biochemistry. 2003 Mar 25;42(11):3255-64
references.pmid: 12641457
references.citation: Cancer Res. 2001 Dec 1;61(23):8554-63
references.pmid: 11731442
references.citation: DNA Repair (Amst). 2008 Oct 1;7(10):1680-92
references.pmid: 18644470
references.citation: J Biol Chem. 2007 Mar 2;282(9):6582-7
references.pmid: 17189255
references.citation: J Biol Chem. 1997 Oct 31;272(44):28073-80
references.pmid: 9346961
references.citation: FEBS Lett. 2010 Sep 10;584(17):3717-24
references.pmid: 20493860
references.citation: J Biol Chem. 2009 Sep 4;284(36):24213-22
references.pmid: 19586908
references.citation: J Cell Biol. 2008 Apr 21;181(2):213-26
references.pmid: 18411307
references.citation: Mol Cell Biol. 2007 Mar;27(5):1581-91
references.pmid: 17158925
references.citation: Nucleic Acids Res. 1998 Dec 1;26(23):5388-93
references.pmid: 9826763
references.citation: Cancer Res. 2000 Jun 15;60(12):3299-304
references.pmid: 10866324
references.citation: Biochem Biophys Res Commun. 2009 Mar 27;381(1):59-64
references.pmid: 19351595
references.citation: J Biol Chem. 2008 Feb 1;283(5):2564-74
references.pmid: 17977830
references.citation: EMBO J. 2006 Dec 13;25(24):5775-82
references.pmid: 17124492
references.citation: Cell. 1992 May 1;69(3):457-70
references.pmid: 1581961
references.citation: J Cell Biol. 2007 Oct 22;179(2):183-6
references.pmid: 17938249
references.citation: J Biol Chem. 2004 Sep 17;279(38):39408-13
references.pmid: 15258142
references.citation: Genes Dev. 2002 Sep 15;16(18):2333-8
references.pmid: 12231622
references.citation: J Biol Chem. 2006 Sep 22;281(38):27784-93
references.pmid: 16857680
references.citation: Nucleic Acids Res. 1999 Dec 15;27(24):4679-86
references.pmid: 10572166
references.citation: J Biol Chem. 2005 Oct 7;280(40):33839-46
references.pmid: 16093244
references.citation: J Biol Chem. 2001 Nov 9;276(45):42462-7
references.pmid: 11571274
references.citation: Oncogene. 2005 Feb 3;24(6):949-61
references.pmid: 15592499
references.citation: Science. 1999 Nov 5;286(5442):1162-6
references.pmid: 10550055
references.citation: Cell Cycle. 2007 Apr 15;6(8):931-42
references.pmid: 17457059
references.citation: J Biol Chem. 2001 May 18;276(20):17276-80
references.pmid: 11278964
references.citation: Mol Cell Biol. 2007 Dec;27(24):8502-9
references.pmid: 17923702
references.citation: J Cell Biol. 2010 Jul 26;190(2):197-207
references.pmid: 20660628
references.citation: Nucleic Acids Res. 2004 Aug 16;32(14):4351-7
references.pmid: 15314205