title: Deoxycytidine kinase augments ATM-Mediated DNA repair and contributes to radiation resistance.
abstract: Efficient and adequate generation of deoxyribonucleotides is critical to successful DNA repair. We show that ataxia telangiectasia mutated (ATM) integrates the DNA damage response with DNA metabolism by regulating the salvage of deoxyribonucleosides. Specifically, ATM phosphorylates and activates deoxycytidine kinase (dCK) at serine 74 in response to ionizing radiation (IR). Activation of dCK shifts its substrate specificity toward deoxycytidine, increases intracellular dCTP pools post IR, and enhances the rate of DNA repair. Mutation of a single serine 74 residue has profound effects on murine T and B lymphocyte development, suggesting that post-translational regulation of dCK may be important in maintaining genomic stability during hematopoiesis. Using [(18)F]-FAC, a dCK-specific positron emission tomography (PET) probe, we visualized and quantified dCK activation in tumor xenografts after IR, indicating that dCK activation could serve as a biomarker for ATM function and DNA damage response in vivo. In addition, dCK-deficient leukemia cell lines and murine embryonic fibroblasts exhibited increased sensitivity to IR, indicating that pharmacologic inhibition of dCK may be an effective radiosensitization strategy.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California, United States of America; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Yuri L
authors.initials: YL
authors.lastname: Bunimovich
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Evan
authors.initials: E
authors.lastname: Nair-Gill
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Mireille
authors.initials: M
authors.lastname: Riedinger
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Melissa N
authors.initials: MN
authors.lastname: McCracken
authors.affiliation: Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Donghui
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Jami
authors.initials: J
authors.lastname: McLaughlin
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California, United States of America; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, California, United States of America; Ahmanson Translational Imaging Division, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Caius G
authors.initials: CG
authors.lastname: Radu
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California, United States of America; Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, California, United States of America; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, California, United States of America; Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Owen N
authors.initials: ON
authors.lastname: Witte
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects*; D003841:Deoxycytidine / Q000378:metabolism; D003842:Deoxycytidine Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003853:Deoxyribonucleosides / Q000378:metabolism; D042822:Genomic Instability; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology
chemical_list: D003853:Deoxyribonucleosides; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; D064007:Ataxia Telangiectasia Mutated Proteins
references.citation: Eur J Cancer. 1999 Dec;35(13):1773-82
references.pmid: 10673991
references.citation: Science. 2010 Oct 22;330(6003):517-21
references.pmid: 20966255
references.citation: Invest New Drugs. 1996;14(3):257-63
references.pmid: 8958180
references.citation: Oncol Rep. 2006 Oct;16(4):901-5
references.pmid: 16969512
references.citation: FEBS Lett. 2008 Mar 5;582(5):720-4
references.pmid: 18258203
references.citation: Nat Med. 2008 Jul;14(7):783-8
references.pmid: 18542051
references.citation: J Nucl Med. 1986 Feb;27(2):235-8
references.pmid: 3712040
references.citation: Mutat Res. 2004 Oct 4;554(1-2):351-64
references.pmid: 15450431
references.citation: Annu Rev Biochem. 1988;57:349-74
references.pmid: 3052277
references.citation: Clin Cancer Res. 2001 Nov;7(11):3559-66
references.pmid: 11705877
references.citation: Biochem Pharmacol. 2003 Feb 15;65(4):573-80
references.pmid: 12566084
references.citation: Int J Radiat Oncol Biol Phys. 1997 Jan 15;37(2):259-67
references.pmid: 9069295
references.citation: Annu Rev Biochem. 2008;77:229-57
references.pmid: 18275380
references.citation: Nat Rev Mol Cell Biol. 2008 Aug;9(8):616-27
references.pmid: 18594563
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2847-52
references.pmid: 19196993
references.citation: Nucleosides Nucleotides Nucleic Acids. 2004 Oct;23(8-9):1363-5
references.pmid: 15571259
references.citation: Science. 2007 May 25;316(5828):1160-6
references.pmid: 17525332
references.citation: Nucleosides Nucleotides Nucleic Acids. 2010 Jun;29(4-6):363-9
references.pmid: 20544521
references.citation: Biochim Biophys Acta. 1996 Oct 29;1286(3):153-81
references.pmid: 8982282
references.citation: Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1531-5
references.pmid: 1996353
references.citation: Cancer Res. 2004 Dec 15;64(24):9152-9
references.pmid: 15604286
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18519-24
references.pmid: 19015526
references.citation: Oncogene. 2009 May 28;28(21):2173-84
references.pmid: 19398949
references.citation: DNA Repair (Amst). 2009 Nov 2;8(11):1258-63
references.pmid: 19713159
references.citation: J Biomol Screen. 2010 Jan;15(1):72-9
references.pmid: 19959816
references.citation: Biochem Pharmacol. 2007 Feb 1;73(3):351-8
references.pmid: 17137556
references.citation: J Exp Med. 1996 Dec 1;184(6):2327-39
references.pmid: 8976187
references.citation: Cancer Metastasis Rev. 2004 Aug-Dec;23(3-4):311-22
references.pmid: 15197331
references.citation: Nat Rev Immunol. 2010 Sep;10(9):657-63
references.pmid: 20725107
references.citation: Biochemistry. 2011 Apr 12;50(14):2870-80
references.pmid: 21351740
references.citation: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):781-96
references.pmid: 15279764
references.citation: Eur J Cancer. 1999 Dec;35(13):1862-7
references.pmid: 10674004
references.citation: Nucleic Acids Res. 2012 Oct;40(19):9621-32
references.pmid: 22850745
references.citation: EMBO J. 2011 Feb 2;30(3):546-55
references.pmid: 21157431
references.citation: J Biol Chem. 2006 Mar 24;281(12):7834-41
references.pmid: 16436374
references.citation: Nat Rev Mol Cell Biol. 2013 Apr;14(4):197-210
references.pmid: 23847781
references.citation: Gene Ther. 1994 Mar;1(2):136-8
references.pmid: 7584069
references.citation: Chem Rev. 2009 Jul;109(7):2929-50
references.pmid: 19545147
references.citation: Cell. 1996 Jul 12;86(1):159-71
references.pmid: 8689683
references.citation: J Biol Chem. 2006 Feb 24;281(8):4887-93
references.pmid: 16361699
references.citation: J Nucl Med. 2010 Jul;51(7):1092-8
references.pmid: 20554721
references.citation: Biochem Pharmacol. 2004 Mar 1;67(5):947-55
references.pmid: 15104248
references.citation: Nucleosides Nucleotides Nucleic Acids. 2006;25(9-11):1147-51
references.pmid: 17065080
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5551-6
references.pmid: 20080663
references.citation: EMBO J. 2003 Oct 15;22(20):5612-21
references.pmid: 14532133
references.citation: FASEB J. 2006 Jul;20(9):1300-14
references.pmid: 16816105
references.citation: Radiat Res. 2011 Oct;176(4):425-33
references.pmid: 21756082
references.citation: Nature. 2006 Jul 27;442(7101):466-70
references.pmid: 16799570
references.citation: Bioorg Med Chem Lett. 2004 Dec 20;14(24):6083-7
references.pmid: 15546735
references.citation: J Exp Med. 2012 Nov 19;209(12):2215-28
references.pmid: 23148236
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17456-61
references.pmid: 15505216
references.citation: Radiat Res. 2010 Nov;174(5):574-81
references.pmid: 20954859
references.citation: Immunity. 2006 Jan;24(1):53-64
references.pmid: 16413923
references.citation: Immunity. 2007 Jun;26(6):703-14
references.pmid: 17582343
references.citation: Methods Mol Biol. 2009;554:371-81
references.pmid: 19513685
references.citation: Cell. 1997 Oct 31;91(3):325-34
references.pmid: 9363941
references.citation: Radiat Oncol. 2013 Sep 26;8:223
references.pmid: 24066967
references.citation: J Exp Med. 1991 May 1;173(5):1213-25
references.pmid: 1827140
references.citation: Cell Mol Life Sci. 2011 Feb;68(4):687-96
references.pmid: 20717837
references.citation: Nucleosides Nucleotides Nucleic Acids. 2006;25(9-11):1141-6
references.pmid: 17065079
references.citation: Nat Genet. 2003 Apr;33(4):497-501
references.pmid: 12640452
references.citation: J Clin Invest. 2007 Sep;117(9):2723-34
references.pmid: 17786248
references.citation: Int J Radiat Biol. 1999 Aug;75(8):1005-13
references.pmid: 10465366
references.citation: Nat Rev Mol Cell Biol. 2008 Oct;9(10):759-69
references.pmid: 18813293
references.citation: Mech Ageing Dev. 2009 Jan-Feb;130(1-2):46-53
references.pmid: 18479735
references.citation: EMBO J. 2006 Dec 13;25(24):5775-82
references.pmid: 17124492
references.citation: Adv Exp Med Biol. 1998;431:525-9
references.pmid: 9598122
references.citation: FEBS Lett. 2011 Jun 6;585(11):1625-39
references.pmid: 21570395
references.citation: Cancer Lett. 2007 Aug 8;253(1):68-73
references.pmid: 17350163
references.citation: Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):789-93
references.pmid: 9845097
references.citation: Biochem Pharmacol. 2004 Jul 1;68(1):95-103
references.pmid: 15183121
references.citation: PLoS One. 2012;7(3):e30541
references.pmid: 22412831
references.citation: Biochem Pharmacol. 2003 Jun 15;65(12):2031-9
references.pmid: 12787883
references.citation: Annu Rev Biochem. 2004;73:39-85
references.pmid: 15189136
references.citation: Exp Gerontol. 2009 Oct;44(10):676-84
references.pmid: 19602431
references.citation: Nat Struct Biol. 2003 Jul;10(7):513-9
references.pmid: 12808445
references.citation: J Proteome Res. 2011 May 6;10(5):2651-7
references.pmid: 21322649
references.citation: Mol Imaging Biol. 2005 Nov-Dec;7(6):393-402
references.pmid: 16261425
references.citation: Clin Cancer Res. 2004 Aug 15;10(16):5614-21
references.pmid: 15328204