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Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress
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 pa...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501349/ https://www.ncbi.nlm.nih.gov/pubmed/23148236 http://dx.doi.org/10.1084/jem.20121061 |
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author | Austin, Wayne R. Armijo, Amanda L. Campbell, Dean O. Singh, Arun S. Hsieh, Terry Nathanson, David Herschman, Harvey R. Phelps, Michael E. Witte, Owen N. Czernin, Johannes Radu, Caius G. |
author_facet | Austin, Wayne R. Armijo, Amanda L. Campbell, Dean O. Singh, Arun S. Hsieh, Terry Nathanson, David Herschman, Harvey R. Phelps, Michael E. Witte, Owen N. Czernin, Johannes Radu, Caius G. |
author_sort | Austin, Wayne R. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3501349 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-35013492013-05-19 Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress Austin, Wayne R. Armijo, Amanda L. Campbell, Dean O. Singh, Arun S. Hsieh, Terry Nathanson, David Herschman, Harvey R. Phelps, Michael E. Witte, Owen N. Czernin, Johannes Radu, Caius G. J Exp Med Article 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. The Rockefeller University Press 2012-11-19 /pmc/articles/PMC3501349/ /pubmed/23148236 http://dx.doi.org/10.1084/jem.20121061 Text en © 2012 Austin et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Article Austin, Wayne R. Armijo, Amanda L. Campbell, Dean O. Singh, Arun S. Hsieh, Terry Nathanson, David Herschman, Harvey R. Phelps, Michael E. Witte, Owen N. Czernin, Johannes Radu, Caius G. Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress |
title | Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress |
title_full | Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress |
title_fullStr | Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress |
title_full_unstemmed | Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress |
title_short | Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress |
title_sort | nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501349/ https://www.ncbi.nlm.nih.gov/pubmed/23148236 http://dx.doi.org/10.1084/jem.20121061 |
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