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

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 de...

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Autores principales:	Yuri L Bunimovich, Evan Nair-Gill, Mireille Riedinger, Melissa N McCracken, Donghui Cheng, Jami McLaughlin, Caius G Radu, Owen N Witte
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4f7f2fb282054ae599f251086f332978
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spelling	oai:doaj.org-article:4f7f2fb282054ae599f251086f3329782021-11-25T06:05:38ZDeoxycytidine kinase augments ATM-Mediated DNA repair and contributes to radiation resistance.1932-620310.1371/journal.pone.0104125https://doaj.org/article/4f7f2fb282054ae599f251086f3329782014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25101980/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Efficient 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.Yuri L BunimovichEvan Nair-GillMireille RiedingerMelissa N McCrackenDonghui ChengJami McLaughlinCaius G RaduOwen N WittePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 8, p e104125 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yuri L Bunimovich Evan Nair-Gill Mireille Riedinger Melissa N McCracken Donghui Cheng Jami McLaughlin Caius G Radu Owen N Witte Deoxycytidine kinase augments ATM-Mediated DNA repair and contributes to radiation resistance.
description	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.
format	article
author	Yuri L Bunimovich Evan Nair-Gill Mireille Riedinger Melissa N McCracken Donghui Cheng Jami McLaughlin Caius G Radu Owen N Witte
author_facet	Yuri L Bunimovich Evan Nair-Gill Mireille Riedinger Melissa N McCracken Donghui Cheng Jami McLaughlin Caius G Radu Owen N Witte
author_sort	Yuri L Bunimovich
title	Deoxycytidine kinase augments ATM-Mediated DNA repair and contributes to radiation resistance.
title_short	Deoxycytidine kinase augments ATM-Mediated DNA repair and contributes to radiation resistance.
title_full	Deoxycytidine kinase augments ATM-Mediated DNA repair and contributes to radiation resistance.
title_fullStr	Deoxycytidine kinase augments ATM-Mediated DNA repair and contributes to radiation resistance.
title_full_unstemmed	Deoxycytidine kinase augments ATM-Mediated DNA repair and contributes to radiation resistance.
title_sort	deoxycytidine kinase augments atm-mediated dna repair and contributes to radiation resistance.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/4f7f2fb282054ae599f251086f332978
work_keys_str_mv	AT yurilbunimovich deoxycytidinekinaseaugmentsatmmediateddnarepairandcontributestoradiationresistance AT evannairgill deoxycytidinekinaseaugmentsatmmediateddnarepairandcontributestoradiationresistance AT mireilleriedinger deoxycytidinekinaseaugmentsatmmediateddnarepairandcontributestoradiationresistance AT melissanmccracken deoxycytidinekinaseaugmentsatmmediateddnarepairandcontributestoradiationresistance AT donghuicheng deoxycytidinekinaseaugmentsatmmediateddnarepairandcontributestoradiationresistance AT jamimclaughlin deoxycytidinekinaseaugmentsatmmediateddnarepairandcontributestoradiationresistance AT caiusgradu deoxycytidinekinaseaugmentsatmmediateddnarepairandcontributestoradiationresistance AT owennwitte deoxycytidinekinaseaugmentsatmmediateddnarepairandcontributestoradiationresistance
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Deoxycytidine kinase augments ATM-Mediated DNA repair and contributes to radiation resistance.

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