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PLoS One. 2014 Aug 7;9(8):e104125. doi: 10.1371/journal.pone.0104125. eCollection 2014.

Deoxycytidine kinase augments ATM-Mediated DNA repair and contributes to radiation resistance.

Author information

1
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.
2
Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California, United States of America.
3
Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, California, United States of America.
4
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
5
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.
6
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.

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.

PMID:
25101980
PMCID:
PMC4125169
DOI:
10.1371/journal.pone.0104125
[Indexed for MEDLINE]
Free PMC Article

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