ArticleThe Journal of experimental medicine2012
Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress.
Article in The Journal of experimental medicine, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 92 citations in OpenAlex.
- Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage.bioRxiv : the preprint server for biology · 2026Article
- DREAMS illuminates spatial DNA and RNA modification landscapes.Nature cell biology · 2026Article
- Spatial multi-omics guides ASCT2-targeted delivery of glycolysis inhibitor for cervical cancer suppression and chemoresistance reversal.Journal of advanced research · 2026Article
- Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells.Cell death discovery · 2026Article
- Nucleotide salvage, genome instability, and potential therapeutic applications.Nucleic acids research · 2026Review
- Upcycling Fermented Adlay Bran Ethanol Extract Residues Promotes Human Dermal Fibroblast Proliferation and Wound Healing.Journal of microbiology and biotechnology · 2026Article
- Noninvasive in vivo deoxycytidine kinase (dCK)-PET identifies tumor-draining lymph nodes upon immune checkpoint inhibitor therapy.Npj imaging · 2026Article
- Metabolomic Profiling Reveals Distinct Signatures in Primary and Secondary Polycythemia.Metabolites · 2025Article
- Histology-resolved proteomics reveals distinct tumor and stromal profiles in low- and high-grade prostate cancer.Clinical proteomics · 2025Article
- Landscape of targets within nucleoside metabolism for the modification of immune responses.Frontiers in oncology · 2025Review
- Selectively T cell phosphorylation activation of azvudine in the thymus tissue with immune protection effect.Acta pharmaceutica Sinica. B · 2024Article
- Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice.Nature communications · 2024Article
- Impact of GADD45A on Radiation Biodosimetry Using Mouse Peripheral Blood.Radiation research · 2023Article
- NUDT22 promotes cancer growth through pyrimidine salvage.Oncogene · 2023Article
- Oxidized mitochondrial DNA: a protective signal gone awry.Trends in immunology · 2023Review
- Targeting deoxycytidine kinase improves symptoms in mouse models of multiple sclerosis.Immunology · 2023Article
- Germline thymidylate synthase deficiency impacts nucleotide metabolism and causes dyskeratosis congenita.American journal of human genetics · 2022Article
- Different Susceptibility of T and B Cells to Cladribine Depends On Their Levels of Deoxycytidine Kinase Activity Linked to Activation Status.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2022Article
- Targeting nucleotide metabolism: a promising approach to enhance cancer immunotherapy.Journal of hematology & oncology · 2022Review
- Review
3 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.