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

Yuri L. Bunimovich, Evan Nair-Gill, Mireille Riedinger, Melissa N. McCracken, Donghui Cheng, Jami McLaughlin, Caius G. Radu, Owen N. Witte

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17 Scopus citations

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 [18F]-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.

Original languageEnglish (US)
Article numbere104125
JournalPloS one
Volume9
Issue number8
DOIs
StatePublished - Aug 7 2014

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Bunimovich, Y. L., Nair-Gill, E., Riedinger, M., McCracken, M. N., Cheng, D., McLaughlin, J., Radu, C. G., & Witte, O. N. (2014). Deoxycytidine kinase augments ATM-mediated DNA repair and contributes to radiation resistance. PloS one, 9(8), [e104125]. https://doi.org/10.1371/journal.pone.0104125