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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / physiology*
  • B-Lymphocytes / cytology
  • B-Lymphocytes / physiology
  • Cell Line, Tumor
  • DNA Damage
  • DNA Repair / drug effects
  • DNA Repair / radiation effects*
  • Deoxycytidine / metabolism
  • Deoxycytidine Kinase / chemistry
  • Deoxycytidine Kinase / genetics
  • Deoxycytidine Kinase / metabolism*
  • Deoxyribonucleosides / metabolism
  • Genomic Instability
  • Hematopoiesis / genetics
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Substrate Specificity
  • T-Lymphocytes / cytology
  • T-Lymphocytes / physiology

Substances

  • Deoxyribonucleosides
  • Deoxycytidine
  • Deoxycytidine Kinase
  • Ataxia Telangiectasia Mutated Proteins