title: TDP1 promotes assembly of non-homologous end joining protein complexes on DNA.
abstract: The repair of DNA double-strand breaks (DSB) is central to the maintenance of genomic integrity. In tumor cells, the ability to repair DSBs predicts response to radiation and many cytotoxic anti-cancer drugs. DSB repair pathways include homologous recombination and non-homologous end joining (NHEJ). NHEJ is a template-independent mechanism, yet many NHEJ repair products carry limited genetic changes, which suggests that NHEJ includes mechanisms to minimize error. Proteins required for mammalian NHEJ include Ku70/80, the DNA-dependent protein kinase (DNA-PKcs), XLF/Cernunnos and the XRCC4:DNA ligase IV complex. NHEJ also utilizes accessory proteins that include DNA polymerases, nucleases, and other end-processing factors. In yeast, mutations of tyrosyl-DNA phosphodiesterase (TDP1) reduced NHEJ fidelity. TDP1 plays an important role in repair of topoisomerase-mediated DNA damage and 3'-blocking DNA lesions, and mutation of the human TDP1 gene results in an inherited human neuropathy termed SCAN1. We found that human TDP1 stimulated DNA binding by XLF and physically interacted with XLF to form TDP1:XLF:DNA complexes. TDP1:XLF interactions preferentially stimulated TDP1 activity on dsDNA as compared to ssDNA. TDP1 also promoted DNA binding by Ku70/80 and stimulated DNA-PK activity. Because Ku70/80 and XLF are the first factors recruited to the DSB at the onset of NHEJ, our data suggest a role for TDP1 during the early stages of mammalian NHEJ.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, Rockford Health Sciences Campus, 1601 Parkview Avenue, Rockford, IL 61107, USA.
authors.forename: Jinho
authors.initials: J
authors.lastname: Heo
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, Rockford Health Sciences Campus, 1601 Parkview Avenue, Rockford, IL 61107, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, Rockford Health Sciences Campus, 1601 Parkview Avenue, Rockford, IL 61107, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Summerlin
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, Rockford Health Sciences Campus, 1601 Parkview Avenue, Rockford, IL 61107, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Hays
authors.affiliation: University of Manitoba, Department of Pharmacology and Therapeutics, Manitoba Institute of Cell Biology, 675 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0V9.
authors.forename: Sachin
authors.initials: S
authors.lastname: Katyal
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Rockford Health Sciences Campus, 1601 Parkview Avenue, Rockford, IL 61107, USA.
authors.forename: Karin C
authors.initials: KC
authors.lastname: Nitiss
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Rockford Health Sciences Campus, 1601 Parkview Avenue, Rockford, IL 61107, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Nitiss
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, Rockford Health Sciences Campus, 1601 Parkview Avenue, Rockford, IL 61107, USA; Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Rockford Health Sciences Campus, 1601 Parkview Avenue, Rockford, IL 61107, USA. Electronic address: hanakahi@uic.edu.
authors.forename: Leslyn A
authors.initials: LA
authors.lastname: Hanakahi
mesh_terms: D034961:Antigens, Nuclear / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D059766:DNA End-Joining Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D000072200:Ku Autoantigen; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C508551:NHEJ1 protein, human; D004247:DNA; D051747:DNA-Activated Protein Kinase; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; D045643:DNA Repair Enzymes
keywords: DNA-dependent protein kinase (DNA-PK); Ku70/80; Non-homologous end joining (NHEJ); TDP1; XLF
references.citation: Nucleic Acids Res. 2012 Feb;40(4):1868-78
references.pmid: 22287571
references.citation: Mol Cell. 2008 Sep 5;31(5):631-40
references.pmid: 18775323
references.citation: Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2028-33
references.pmid: 21245310
references.citation: J Biol Chem. 1996 Apr 12;271(15):8936-41
references.pmid: 8621537
references.citation: Cell Cycle. 2008 May 15;7(10):1321-5
references.pmid: 18418068
references.citation: J Biol Chem. 1998 Jun 5;273(23):14461-7
references.pmid: 9603959
references.citation: EMBO J. 2004 Oct 1;23(19):3874-85
references.pmid: 15385968
references.citation: Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6958-62
references.pmid: 1495986
references.citation: J Biol Chem. 2011 Sep 16;286(37):32638-50
references.pmid: 21775435
references.citation: Structure. 2002 Feb;10(2):237-48
references.pmid: 11839309
references.citation: J Biol Chem. 2010 Aug 20;285(34):26475-83
references.pmid: 20558749
references.citation: PLoS Genet. 2014 Jan;10(1):e1004086
references.pmid: 24453986
references.citation: J Biol Chem. 1998 Jan 16;273(3):1794-801
references.pmid: 9430729
references.citation: EMBO Rep. 2008 Jan;9(1):91-6
references.pmid: 18064046
references.citation: Curr Opin Cell Biol. 2005 Dec;17(6):568-75
references.pmid: 16226452
references.citation: Mol Cell Biol. 1985 Dec;5(12):3610-6
references.pmid: 3915782
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4057-62
references.pmid: 20160111
references.citation: Annu Rev Biochem. 2010;79:181-211
references.pmid: 20192759
references.citation: DNA Repair (Amst). 2009 May 1;8(5):654-63
references.pmid: 19211312
references.citation: Exp Cell Res. 2014 Nov 15;329(1):18-25
references.pmid: 25017100
references.citation: Cell Cycle. 2011 Jun 15;10(12):1928-35
references.pmid: 21673501
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12009-14
references.pmid: 11572945
references.citation: Mol Cell Biol. 2005 Dec;25(24):10842-52
references.pmid: 16314509
references.citation: DNA Repair (Amst). 2003 Oct 7;2(10):1087-100
references.pmid: 13679147
references.citation: J Biol Chem. 2011 Oct 21;286(42):36368-77
references.pmid: 21885877
references.citation: DNA Repair (Amst). 2002 Mar 28;1(3):225-35
references.pmid: 12509254
references.citation: Nucleic Acids Res. 2010 Apr;38(7):2444-52
references.pmid: 20097655
references.citation: Biochem J. 2011 Jun 15;436(3):559-66
references.pmid: 21463258
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18597-602
references.pmid: 17124166
references.citation: Cell Death Differ. 2012 Apr;19(4):582-91
references.pmid: 21979466
references.citation: Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2022-7
references.pmid: 21245316
references.citation: EMBO J. 2007 Nov 14;26(22):4720-31
references.pmid: 17914460
references.citation: J Biol Chem. 2012 Apr 13;287(16):12848-57
references.pmid: 22375014
references.citation: Nucleic Acids Res. 2012 May;40(9):4168-77
references.pmid: 22223246
references.citation: Nucleic Acids Res. 2014 Apr;42(7):4435-49
references.pmid: 24493735
references.citation: Nucleic Acids Res. 2012 Feb;40(4):1684-94
references.pmid: 22228831
references.citation: J Biol Chem. 2004 Dec 31;279(53):55618-25
references.pmid: 15494395
references.citation: DNA Repair (Amst). 2009 Aug 6;8(8):901-11
references.pmid: 19505854
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1345-50
references.pmid: 15668400
references.citation: Nucleic Acids Res. 2013 Sep;41(16):7793-803
references.pmid: 23775789
references.citation: FEBS Lett. 2011 Mar 23;585(6):841-6
references.pmid: 21349273
references.citation: DNA Repair (Amst). 2007 Jun 1;6(6):712-22
references.pmid: 17241822
references.citation: Nucleic Acids Res. 2014 Mar;42(5):3089-103
references.pmid: 24335147
references.citation: DNA Repair (Amst). 2010 Dec 10;9(12):1307-14
references.pmid: 21030321
references.citation: ISRN Mol Biol. 2012;2012:null
references.pmid: 24236237
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):19790-5
references.pmid: 21041670
references.citation: Nucleic Acids Res. 2007;35(13):4474-84
references.pmid: 17576665
references.citation: Biochemistry. 2002 Oct 22;41(42):12706-14
references.pmid: 12379113
references.citation: Genes Cells. 2001 Aug;6(8):677-87
references.pmid: 11532027
references.citation: Nature. 2010 Apr 22;464(7292):1214-7
references.pmid: 20383123
references.citation: Nat Commun. 2012;3:733
references.pmid: 22415824
references.citation: Nature. 2011 Jan 13;469(7329):250-4
references.pmid: 21160472
references.citation: Virology. 2008 Dec 20;382(2):163-70
references.pmid: 18952251
references.citation: J Virol. 1994 Jul;68(7):4262-73
references.pmid: 8207801
references.citation: Nat Genet. 2002 Oct;32(2):267-72
references.pmid: 12244316
references.citation: Cell Cycle. 2010 Feb 1;9(3):588-595
references.pmid: 20009512
references.citation: Nucleic Acids Res. 2011 Jul;39(13):5757-67
references.pmid: 21450809
references.citation: J Biol Chem. 2005 Oct 28;280(43):36518-28
references.pmid: 16141202
references.citation: Mol Cell Biol. 2014 Apr;34(8):1380-8
references.pmid: 24469398
references.citation: Trends Biochem Sci. 2011 May;36(5):262-71
references.pmid: 21353781
references.citation: DNA Repair (Amst). 2014 May;17:39-51
references.pmid: 24630899
references.citation: Nucleic Acids Res. 2005;33(1):289-97
references.pmid: 15647511
references.citation: J Biol Chem. 2007 Apr 13;282(15):11155-62
references.pmid: 17317666
references.citation: J Biol Chem. 2005 Jun 10;280(23):22029-35
references.pmid: 15811850
references.citation: Nat Methods. 2006 Feb;3(2):135-9
references.pmid: 16432524
references.citation: EMBO J. 2008 Jan 9;27(1):290-300
references.pmid: 18046455
references.citation: DNA Repair (Amst). 2014 Jul;19:114-29
references.pmid: 24856239
references.citation: Annu Rev Genet. 2005;39:431-51
references.pmid: 16285867
references.citation: Nucleic Acids Res. 2002 Mar 1;30(5):1198-204
references.pmid: 11861912
references.citation: Mol Cancer Res. 2011 Oct;9(10):1366-76
references.pmid: 21856774
references.citation: EMBO J. 2005 Jun 15;24(12):2224-33
references.pmid: 15920477
references.citation: Cold Spring Harb Perspect Biol. 2013 May;5(5):a012757
references.pmid: 23637284
references.citation: J Biol Chem. 2002 Jul 26;277(30):27162-8
references.pmid: 12023295
references.citation: Nucleic Acids Res. 2009 Jul;37(12):4055-62
references.pmid: 19420065
references.citation: J Biol Chem. 2010 Nov 26;285(48):37619-29
references.pmid: 20852255
references.citation: J Biol Chem. 2010 Jan 8;285(2):1414-23
references.pmid: 19893054
references.citation: Science. 1999 Oct 15;286(5439):552-5
references.pmid: 10521354
references.citation: DNA Repair (Amst). 2013 Jun 1;12(6):422-32
references.pmid: 23602515
references.citation: EMBO J. 2009 Dec 2;28(23):3667-80
references.pmid: 19851285
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):8953-8
references.pmid: 16751265
references.citation: Antioxid Redox Signal. 2011 Jun 15;14(12):2531-43
references.pmid: 20698792