| Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress. | |
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MedLine Citation:
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PMID: 23148236 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Nucleotide deficiency causes replication stress (RS) and DNA damage in dividing cells. How nucleotide metabolism is regulated in vivo to prevent these deleterious effects remains unknown. In this study, we investigate a functional link between nucleotide deficiency, RS, and the nucleoside salvage pathway (NSP) enzymes deoxycytidine kinase (dCK) and thymidine kinase (TK1). We show that inactivation of dCK in mice depletes deoxycytidine triphosphate (dCTP) pools and induces RS, early S-phase arrest, and DNA damage in erythroid, B lymphoid, and T lymphoid lineages. TK1(-/-) erythroid and B lymphoid lineages also experience nucleotide deficiency but, unlike their dCK(-/-) counterparts, they still sustain DNA replication. Intriguingly, dCTP pool depletion, RS, and hematopoietic defects induced by dCK inactivation are almost completely reversed in a newly generated dCK/TK1 double-knockout (DKO) mouse model. Using NSP-deficient DKO hematopoietic cells, we identify a previously unrecognized biological activity of endogenous thymidine as a strong inducer of RS in vivo through TK1-mediated dCTP pool depletion. We propose a model that explains how TK1 and dCK "tune" dCTP pools to both trigger and resolve RS in vivo. This new model may be exploited therapeutically to induce synthetic sickness/lethality in hematological malignancies, and possibly in other cancers. |
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Authors:
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Wayne R Austin; Amanda L Armijo; Dean O Campbell; Arun S Singh; Terry Hsieh; David Nathanson; Harvey R Herschman; Michael E Phelps; Owen N Witte; Johannes Czernin; Caius G Radu |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-11-12 |
Journal Detail:
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Title: The Journal of experimental medicine Volume: 209 ISSN: 1540-9538 ISO Abbreviation: J. Exp. Med. Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-20 Completed Date: 2013-01-22 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 2985109R Medline TA: J Exp Med Country: United States |
Other Details:
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Languages: eng Pagination: 2215-28 Citation Subset: IM |
Affiliation:
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Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blotting, Western Bromodeoxyuridine DNA Replication / physiology* Deoxycytidine Kinase / genetics, metabolism Deoxycytosine Nucleotides / metabolism Flow Cytometry Hematopoiesis / physiology* Immunophenotyping Metabolic Networks and Pathways / physiology* Mice Mice, Knockout Models, Biological* Nucleosides / metabolism* Nucleotides / deficiency*, metabolism Stress, Physiological / physiology* Thymidine Kinase / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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5U54 CA119347/CA/NCI NIH HHS; P50 CA86306/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Deoxycytosine Nucleotides; 0/Nucleosides; 0/Nucleotides; 2056-98-6/2'-deoxycytidine 5'-triphosphate; 59-14-3/Bromodeoxyuridine; EC 2.7.1.21/Thymidine Kinase; EC 2.7.1.74/Deoxycytidine Kinase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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