Deoxycytidine Kinase Augments ATM-Mediated DNA Repair and Contributes to Radiation Resistance

PLoS One

Evan Nair-Gill¹  Caius G. Radu²  Mireille Riedinger³  Donghui Cheng³  Owen N. Witte³  Yuri L. Bunimovich³  Melissa N. McCracken³  Jami McLaughlin⁴ 

[1] Crump Institute for Molecular Imaging, 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;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

关键词: DNA repair;    Phosphorylation;    DNA damage;    In vitro kinase assay;    B cells;    Bone marrow transplantation;    Cloning;    Thymocytes;   

DOI  :  10.1371/journal.pone.0104125

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY