Exceptionally long-lived nuclear RNAs

Science, Journal Year: 2024, Volume and Issue: 384(6691), P. 31 - 32

Published: April 4, 2024

RNA labeled in young mice is detected 2 years later adult mouse brains.

Language: Английский

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Characterization of uridine-cytidine kinase like-1 nucleoside kinase activity and its role in tumor growth

Biochemical Journal, Journal Year: 2022, Volume and Issue: 479(11), P. 1149 - 1164

Published: May 18, 2022

Uridine-cytidine kinase like-1 (UCKL-1) is a largely uncharacterized protein with high sequence similarity to other uridine-cytidine kinases (UCKs). UCKs play an important role in the pyrimidine salvage pathway, catalyzing phosphorylation of uridine and cytidine UMP CMP, respectively. Only two human have been identified, UCK1 UCK2. Previous studies shown both enzymes phosphorylate using ATP as phosphate donor. No evaluated potential UCKL-1. We cloned purified UCKL-1 found that it successfully phosphorylated The catalytic efficiency (calculated kcat/KM) was 1.2 × 104 s-1, M-1 for 0.7 cytidine. Our lab has previously up-regulated tumor cells, providing protection against natural killer (NK) cell killing activity. utilized small interfering RNA (siRNA) down-regulate vitro vivo determine effect on growth metastasis. down-regulation YAC-1 lymphoma cells resulted decreased counts increased apoptotic Down-regulation K562 leukemia led primary less dissemination These results identify bona fide therapeutic be target inhibition diminishing or preventing

Language: Английский

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Selective vulnerability of human-induced pluripotent stem cells to dihydroorotate dehydrogenase inhibition during mesenchymal stem/stromal cell purification

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Feb. 6, 2023

The use of induced mesenchymal stem/stromal cells (iMSCs) derived from human pluripotent stem (hiPSCs) in regenerative medicine involves the risk teratoma formation due to hiPSCs contamination iMSCs. Therefore, eradicating remaining undifferentiated is crucial for effectiveness strategy. present study demonstrates Brequinar (BRQ)-induced inhibition dihydroorotate dehydrogenase (DHODH), a key enzyme de novo pyrimidine biosynthesis, selectively induces apoptosis, cell cycle arrest, and differentiation; furthermore, it promotes transcriptional changes prevents growth 3-dimensional hiPSC aggregates. Contrastingly, BRQ-treated iMSCs showed no survival, differentiation potential, or gene expression. results suggest that BRQ potential agent effective purification mixed population hiPSCs, which step successful iMSC-based therapy.

Language: Английский

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DHODH: a promising target in the treatment of T-cell acute lymphoblastic leukemia

Blood Advances, Journal Year: 2023, Volume and Issue: 7(21), P. 6685 - 6701

Published: Aug. 31, 2023

Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis few therapeutic options. With the goal of identifying novel targets, we used data from Dependency Map project to identify dihydroorotate dehydrogenase (DHODH) as one top metabolic dependencies in T-ALL. DHODH catalyzes fourth step de novo pyrimidine nucleotide synthesis. Small molecule inhibition rapidly leads depletion intracellular pools and forces cells rely on extracellular salvage. In absence sufficient salvage, this starvation results DNA RNA synthesis, cell cycle arrest, and, ultimately, death. T lymphoblasts appear be specifically exquisitely sensitive after inhibition. We confirmed sensitivity vitro vivo 3 murine models identified that certain subsets T-ALL seem an increased reliance oxidative phosphorylation when treated inhibitors. Through series assays, show cells, setting starvation, undergo changes their mitochondrial membrane potential may more highly dependent alternative fuel sources. The effect normal development young mice was also examined does not permanently damage developing thymus. These suggest new vulnerability distinguish these other hematopoietic offer exploitable opportunity. availability clinical-grade inhibitors currently human clinical trials suggests for advancing work into clinic.

Language: Английский

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Targeting E2F Sensitizes Prostate Cancer Cells to Drug-Induced Replication Stress by Promoting Unscheduled CDK1 Activity

Cancers, Journal Year: 2022, Volume and Issue: 14(19), P. 4952 - 4952

Published: Oct. 10, 2022

E2F1/E2F2 expression correlates with malignancy in prostate cancer (PCa), but its functional significance remains unresolved. To define the mechanisms governed by E2F PCa, we analyzed contribution of target genes to control genome integrity, and impact modulating activity on PCa progression. We show that silencing or inhibiting induces DNA damage during S phase potentiates 5-FU-induced replication stress cellular toxicity. Inhibition downregulates targets involved nucleotide biosynthesis (TK1, DCK, TYMS), whose is upregulated 5-FU. However, their enzymatic products failed rescue knockdown cells, suggesting additional for function. Interestingly, targeting cells reduced WEE1 resulted premature CDK1 activation phase. CDK1/CDK2 prevented induced loss, safeguard integrity restraining activity. Importantly, combined inhibition ATR boosted dramatically tumorigenic capacity xenografts. Collectively, combination drugs repair a promising strategy provoke catastrophic levels could be applied treatment.

Language: Английский

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