ABSTRACT
A efficient protocol has been developed for the synthesis of regioselective imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine derivatives through cascade reaction between 2-aminopyridine, arylelglyoxal, and 4-hydroxypyran via three-component reaction to prepare targeted compounds with good to excellent yields. The advantages of this transformation are a catalyst-free reaction, green solvent, operationally simple, scalable, and eco-friendly. The product collects with simple filtration which avoided tedious and expensive purification techniques. In addition, computational studies like molecular docking were conducted to provide the theoretical possibilities of binding these types of synthesized compounds to the VEGFR2 receptors as potential key inhibitors of tumor cell growth and angiogenesis.
Subject(s)
Pyridines , Molecular Docking Simulation , Pyridines/chemistry , Solvents , CatalysisABSTRACT
We have developed a simple novel ring-closure and ring-opening pathway using an organo-base system for the synthesis of highly substituted dihydrofurofuran and furan frameworks via a triethylamine-catalyzed one-pot three-component reaction. The protocol involved a Knoevenagel and Michael adduct via Paal-Knorr cyclization with aromatic/aliphatic glyoxal and 2-cyanoacetophenone under mild and heating conditions with excellent yields through a simple filtration method. The merits of this methodology, including the use of easily available feedstocks and an inexpensive catalyst, Gram-scale synthesis, wide functional group tolerance, an open-air reaction setup, and no need for workup and column-chromatography procedures, make the developed methodology a practical way to access dihydrofurofurans and functionalized furans.
ABSTRACT
Mammalian development, adult tissue homeostasis and the avoidance of severe diseases including cancer require a properly orchestrated cell cycle, as well as error-free genome maintenance. The key cell-fate decision to replicate the genome is controlled by two major signalling pathways that act in parallel-the MYC pathway and the cyclin D-cyclin-dependent kinase (CDK)-retinoblastoma protein (RB) pathway1,2. Both MYC and the cyclin D-CDK-RB axis are commonly deregulated in cancer, and this is associated with increased genomic instability. The autophagic tumour-suppressor protein AMBRA1 has been linked to the control of cell proliferation, but the underlying molecular mechanisms remain poorly understood. Here we show that AMBRA1 is an upstream master regulator of the transition from G1 to S phase and thereby prevents replication stress. Using a combination of cell and molecular approaches and in vivo models, we reveal that AMBRA1 regulates the abundance of D-type cyclins by mediating their degradation. Furthermore, by controlling the transition from G1 to S phase, AMBRA1 helps to maintain genomic integrity during DNA replication, which counteracts developmental abnormalities and tumour growth. Finally, we identify the CHK1 kinase as a potential therapeutic target in AMBRA1-deficient tumours. These results advance our understanding of the control of replication-phase entry and genomic integrity, and identify the AMBRA1-cyclin D pathway as a crucial cell-cycle-regulatory mechanism that is deeply interconnected with genomic stability in embryonic development and tumorigenesis.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cyclin D/metabolism , Genomic Instability , S Phase , Animals , Cell Line , Cell Proliferation , Checkpoint Kinase 1/antagonists & inhibitors , Cyclin-Dependent Kinases/metabolism , DNA Replication , Gene Expression Regulation, Developmental , Genes, Tumor Suppressor , Humans , Mice , Mice, Knockout , Synthetic Lethal MutationsABSTRACT
D-type cyclins are central regulators of the cell division cycle and are among the most frequently deregulated therapeutic targets in human cancer1, but the mechanisms that regulate their turnover are still being debated2,3. Here, by combining biochemical and genetics studies in somatic cells, we identify CRL4AMBRA1 (also known as CRL4DCAF3) as the ubiquitin ligase that targets all three D-type cyclins for degradation. During development, loss of Ambra1 induces the accumulation of D-type cyclins and retinoblastoma (RB) hyperphosphorylation and hyperproliferation, and results in defects of the nervous system that are reduced by treating pregnant mice with the FDA-approved CDK4 and CDK6 (CDK4/6) inhibitor abemaciclib. Moreover, AMBRA1 acts as a tumour suppressor in mouse models and low AMBRA1 mRNA levels are predictive of poor survival in cancer patients. Cancer hotspot mutations in D-type cyclins abrogate their binding to AMBRA1 and induce their stabilization. Finally, a whole-genome, CRISPR-Cas9 screen identified AMBRA1 as a regulator of the response to CDK4/6 inhibition. Loss of AMBRA1 reduces sensitivity to CDK4/6 inhibitors by promoting the formation of complexes of D-type cyclins with CDK2. Collectively, our results reveal the molecular mechanism that controls the stability of D-type cyclins during cell-cycle progression, in development and in human cancer, and implicate AMBRA1 as a critical regulator of the RB pathway.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cell Division , Cyclin D1/metabolism , Adaptor Proteins, Signal Transducing/genetics , Animals , CRISPR-Cas Systems , Cyclin D2/metabolism , Cyclin D3/metabolism , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Female , Gene Knockout Techniques , Genes, Tumor Suppressor , HCT116 Cells , HEK293 Cells , Humans , Male , Mice , Neoplasms/genetics , Ubiquitin/metabolismABSTRACT
Owing to their unique topology and physical properties, micelles based on miktoarm amphiphilic star block copolymers play an important role in the biomedical field for drug delivery. Herein, we developed a series of AB2-type poly(D,L-lactide-co-glycolide)-b-poly(N-acryloyl morpholine) (PLGA-b-PNAM2) miktoarm star block copolymers by reversible addition-fragmentation chain-transfer polymerization and ring-opening copolymerization. The resulting miktoarm star polymers were investigated by 1H NMR spectroscopy and gel permeation chromatography. The critical micellar concentration value of the micelles increases with an increase in PNAM block length. As revealed by transmission electron microscopy and dynamic light scattering, the amphiphilic miktoarm star block copolymers can self-assemble to form spherical micellar aggregates in water. The anticancer drug doxorubicin (DOX) was encapsulated by polymeric micelles; the drug-loading efficiency and drug-loading content of the DOX-loaded micelles were 81.7% and 9.1%, respectively. Acidic environments triggered the dissociation of the polymeric micelles, which led to the more release of DOX in pH 6.4 than pH 7.4. The amphiphilic PLGA-b-PNAM2 miktoarm star block copolymers may have broad application as nanocarriers for controlled drug delivery.
ABSTRACT
In this article, a drug delivery system with a near-infrared (NIR) light-responsive feature was successfully prepared using a block copolymer poly(ethylene oxide)-b-poly(glycidyl methacrylate)-azide (PEO-b-PGMA-N3) and a cross-linker containing a Se-Se bond through "click" chemistry. Doxorubicin (DOX) was loaded into the core-cross-linked (CCL) micelles of the block copolymer along with indocyanine green (ICG) as a generator of reactive oxygen species (ROS). During NIR light exposure, ROS were generated by ICG and attacked the Se-Se bond of the cross-linker, leading to de-crosslinking of the CCL micelles. After NIR irradiation, the CCL micelles were continuously disrupted, which can be a good indication for effective drug release. Photothermal analysis showed that the temperature elevation during NIR exposure was negligible, thus safe for normal cells. In vitro drug release tests demonstrated that the drug release from diselenide CCL micelles could be controlled by NIR irradiation and affected by the acidity of the environment.
ABSTRACT
A concise and efficient one-pot synthesis of novel N-fused tricyclic derivatives has been developed by using the Groebke-Blackburn-Bienaymé (GBB) reaction, which involved the reaction of 3-amino-1H-indazoles, aldehydes and isonitriles to afford 2-aryl-5H-imidazo[1,2-b]indazol-3-amine derivatives via a formal [4 + 1] cycloaddition reaction. Furthermore, we describe an unprecedented reaction of chromone-3-carboxaldehydes with 3-amino-1H-indazoles to afford (2-hydroxyphenyl)(pyrimido[1,2-b]indazol-3-yl)methanones in one-pot at ambient temperature. This protocol features a robust method for the one-step construction of new tricyclic rings, column chromatography free methods with a clean reaction profile, high yields, operational simplicity and it tolerates a diverse collection of reactants.
ABSTRACT
In response to nutrient deprivation, the cell mobilizes an extensive amount of membrane to form and grow the autophagosome, allowing the progression of autophagy. By providing membranes and stimulating LC3 lipidation, COPII (Coat Protein Complex II) promotes autophagosome biogenesis. Here, we show that the F-box protein FBXW5 targets SEC23B, a component of COPII, for proteasomal degradation and that this event limits the autophagic flux in the presence of nutrients. In response to starvation, ULK1 phosphorylates SEC23B on Serine 186, preventing the interaction of SEC23B with FBXW5 and, therefore, inhibiting SEC23B degradation. Phosphorylated and stabilized SEC23B associates with SEC24A and SEC24B, but not SEC24C and SEC24D, and they re-localize to the ER-Golgi intermediate compartment, promoting autophagic flux. We propose that, in the presence of nutrients, FBXW5 limits COPII-mediated autophagosome biogenesis. Inhibition of this event by ULK1 ensures efficient execution of the autophagic cascade in response to nutrient starvation.
Subject(s)
Autophagy-Related Protein-1 Homolog/metabolism , Autophagy , Epithelial Cells/physiology , F-Box Proteins/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Macrophages/physiology , Vesicular Transport Proteins/metabolism , Cell Line , Humans , Phosphorylation , Protein Interaction Maps , Protein Processing, Post-Translational , ProteolysisABSTRACT
The hybrid material consisting of multi walled carbon nanotubes (MWNTs) and poly(2-hydroxyethylmethacrylate-co-methylmethacrylate) [poly(HEMA-co-MMA)] was synthesized by a combination of RAFT and Click chemistry. In the primary stage, the copolymer poly(HEMA-co-MMA) was prepared by applying RAFT technique. Alkynyl side groups were incorporated onto the poly(HEMA-co-MMA) backbone by esterification reaction. Then, MWNTs-N3 was prepared by treating MWNTs with 4-azidobutylamine. The click coupling reaction between azide-functionalized MWNTs (MWNTs-N3) and the alkyne-functionalized random copolymer ((HEMA-co-MMA)-Alkyne) with the Cu(I)-catalyzed [3+2] Huisgen cycloaddition afforded the hybrid compound. The structure and properties of poly(MMA-co-HEMA)-g-MWNTs were investigated by FT-IR, EDX and TGA measurements. The copolymer brushes were observed to be immobilized onto the functionalized MWNTs by SEM and TEM analysis.
Subject(s)
Click Chemistry , Methylmethacrylates/chemistry , Nanotubes, Carbon , Polyhydroxyethyl Methacrylate/chemistry , Microscopy, Electron, Scanning , Microscopy, Electron, Transmission , Proton Magnetic Resonance Spectroscopy , Spectroscopy, Fourier Transform Infrared , ThermogravimetryABSTRACT
In continuation of previous efforts to investigate the biological potency of tetrahydropyridinol derivatives, the present study synthesized three target compounds: N-(bromoacetyl)-3-carboxyethyl-2,6-diphenyl-4-O-(pentafluorobenzoyl)-Δ3-tetra-hydropyridine (5a), N-(chloroacetyl)-3-carboxyethyl-2,6-diphenyl-4-O-(pentafluorobenzoyl)-Δ3-tetrahydropyridine (5b) and N-(2-bromopropanoyl)-3-carboxyethyl-2,6-diphenyl-4-O-(pentafluorobenzoyl)-Δ3-tetrahydropyridine (5c), and examined their anticancer potency. Experiments were performed using the Sk-Hep1 and Hep3B human hepatocellular carcinoma cell lines and MDA-MB-231 breast adenocarcinoma cell line. Among the three compounds, 5a and 5b were comparably and significantly cytotoxic to the Sk-Hep1, Hep3B and MDA-MB-231 cells. The highest level of cytotoxicity was detected in theSk-Hep1 cells with half maximal inhibitory concentrations for compounds 5a and 5b at 12 and 6 µM, respectively. These two compounds induced cell cycle arrest in the Sk-Hep1 and MDA-MB-231 cells through the downregulation of ß-catenin and upregulation of glycogen synthase kinase-3ß and E-cadherin. By contrast, 5a and 5b induced G1 arrest in the Hep3B cells by modulating the p21 and p27 cell cycle regulatory molecules and cyclin-dependent kinase 2. In addition, 5a and 5b significantly inhibited the invasion of Sk-Hep1 and MDA-MB-231 cells. These results suggested that the 5a and 5b compounds induce cell cycle arrest by suppressing Wnt/ß-catenin signaling in highly invasive Sk-Hep1 and MDA-MB-231 cells, and by inducing p53 independent cell cycle arrest in Hep3B cells.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Piperidines/pharmacology , Wnt Signaling Pathway/drug effects , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Breast/drug effects , Breast/metabolism , Breast/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Liver/drug effects , Liver/metabolism , Liver/pathology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Neoplasm Invasiveness/pathology , Neoplasm Invasiveness/prevention & control , Piperidines/chemistry , beta Catenin/metabolismABSTRACT
A new environmentally benign and highly convergent protocol for the synthesis of indolyl 4H-chromene derivatives has been developed. This one-pot three-component condensation reaction of salicylaldehyde, cyclic 1,3-diketones, and indole is promoted by PS-PTSA as a reusable heterogeneous acid catalyst under solvent-free conditions. This protocol demonstrates several notable advantages such as that the catalyst is readily available and can be recovered and reused for at least five runs without any significant impact on product yields, high atom economy, excellent yields, and efficiency of producing three new bonds (two C-C and one C-O) and one stereo center in a single operation.
Subject(s)
Benzenesulfonates/chemistry , Benzopyrans/chemistry , Polystyrenes/chemistry , Solvents/chemistry , Benzopyrans/chemical synthesisABSTRACT
Hybrid materials of ß-cyclodextrin multi-decorated halloysite nanotubes (HNTs-g-ßCD) were prepared by a facile route, which showed high efficiency for catalysis and dye adsorption. Initially, the surface of halloysite nanotubes (HNTs) was modified with poly(glycidyl methacrylate) by the reversible addition fragmentation chain transfer (RAFT) polymerization of glycidyl methacrylate having epoxy groups as a monomer. Subsequently, ß-cyclodextrin was conjugated with the modified HNTs to produce HNTs-g-ßCD by the epoxide ring-opening reaction of mono-6-deoxy-6-hexanediamine-ß-cyclodextrin. The nanocomposites were characterized by FT-IR, TGA, SEM, and TEM. The HNTs-g-ßCD composites could be used as a nano adsorbent for methylene blue and a catalyst in the oxidation reaction of benzyl alcohol owing to the unique structure of ß-cyclodextrin. The HNTs-g-ßCD shows promiseas potential multi-functional materials by a combination of ß-cyclodextrin and HNTs properties.
Subject(s)
Aluminum Silicates/chemistry , Coloring Agents/isolation & purification , Nanoparticles/chemistry , Water Pollutants, Chemical/isolation & purification , Water Purification/methods , beta-Cyclodextrins/chemistry , Adsorption , Catalysis , Clay , Coloring Agents/chemistry , Materials Testing , Methylene Blue/isolation & purification , Nanoparticles/ultrastructure , Nanopores/ultrastructure , Particle Size , Porosity , Ultrafiltration/methods , Water/chemistryABSTRACT
A series of diverse polyfunctionalized triheterocyclic benzothiazoles were easily prepared in excellent yields via the Biginelli reaction of 2-aminobenzothiazole with substituted benzaldehydes and α-methylene ketones using FeF(3) as an expeditious catalyst under solvent-free conditions. The protocol provides a practical and straightforward approach toward highly functionalized triheterocyclic benzothiazole derivatives in excellent yields. The reaction was conveniently promoted by FeF(3) and the catalyst could be recovered easily after the reaction and reused without any loss of its catalytic activity. The advantageous features of this methodology are high atom economy, operational simplicity, shorter reaction time, convergence, and facile automation.
Subject(s)
Benzothiazoles/chemistry , Benzothiazoles/chemical synthesis , Carbon/chemistry , Ferric Compounds/chemistry , Fluorides/chemistry , Nitrogen/chemistry , Catalysis , Chemistry Techniques, SyntheticABSTRACT
The crystal structure of the title compound, C9H9N3O2, features N-Hâ¯N and C-Hâ¯O inter-actions. The N-Hâ¯N inter-action generates a chain running along the a axis and the C-Hâ¯O inter-action generates a chain along the c axis. An intra-molecular C-Hâ¯O inter-action is also observed.
ABSTRACT
Nanocomposites of graphene nanosheets and poly(diphenylamine) (graphene-PDPA) were synthesized via the in-situ oxidative polymerization of diphenylamine in a sulphuric acid medium. First, graphite oxide (GO) was prepared by oxidation of natural graphite using the modified Hummer's method and subsequently reduced using hydrazine monohydrate. The as-prepared graphene sheets were noncovalently grafted with PDPA using ammonium peroxydisulphate as an oxidant. During the polymerization, graphene sheets were homogeneously dispersed in the PDPA matrix. The formation of the hybrid material was confirmed by FTIR, XPS, TGA, HRTEM, FESEM and XRD measurements. XPS analysis revealed the removal of oxygen functionality from the GO surface after reduction and the bonding structure of the reduced hybrids. In addition, the nanocomposites showed better thermal properties due to the intrinsic property of the graphene sheets.
Subject(s)
Crystallization/methods , Graphite/chemistry , Membranes, Artificial , Nanostructures/chemistry , Nanostructures/ultrastructure , Phenylenediamines/chemistry , Macromolecular Substances/chemistry , Materials Testing , Molecular Conformation , Particle Size , Surface PropertiesABSTRACT
We have previously reported that N-acetylcysteine (NAC) not only delayed apoptosis but also enhanced the production of recombinant erythropoietin (EPO) in Chinese hamster ovary (CHO) cell culture. To investigate the production enhancement mechanism, the effects of similar thiolreducing agents were studied. Intriguingly, all mild reducing agents examined including mercaptoethanesulfonic acid (MESNA), thiolactic acid (TLA), and thioglycolate (TG) were shown to block apoptosis and increase EPO production. A pulse-chase study of EPO secretion revealed that all four thiol-reducing agents increased the EPO secretion rate; among them TLA showed the highest rate. In terms of product quality, the sialic acid content of the glycoprotein is one of the most important factors. It was reported that a number of glycoproteins produced by CHO cells often have incomplete sialylation, particularly under high-producing conditions. Human alpha2,3-sialyltransferase (alpha2,3-ST) was introduced into EPO-producing CHO cells in order to compensate for the reduced sialylation during supplementation with NAC. When alpha2,3-ST was expressed in the presence of NAC, reduced sialylation was restored and an even more sialylated EPO was produced. Thus, our study is significant in that it offers increased EPO production while still allowing the prevention of decreased sialylation of EPO.
Subject(s)
Erythropoietin/metabolism , Gene Expression , Reducing Agents/metabolism , Sialyltransferases/genetics , Sialyltransferases/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Erythropoietin/genetics , Glycolates/metabolism , Humans , Protein Transport , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Secretory Pathway , Sulfhydryl Compounds/metabolismABSTRACT
F-box proteins and DCAF proteins are the substrate binding subunits of the Skp1-Cul1-F-box protein (SCF) and Cul4-RING protein ligase (CRL4) ubiquitin ligase complexes, respectively. Using affinity purification and mass spectrometry, we determined that the F-box protein FBXO11 interacts with CDT2, a DCAF protein that controls cell-cycle progression, and recruits CDT2 to the SCF(FBXO11)complex to promote its proteasomal degradation. In contrast to most SCF substrates, which exhibit phosphodegron-dependent binding to F-box proteins, CDK-mediated phosphorylation of Thr464 present in the CDT2 degron inhibits recognition by FBXO11. Finally, our results show that the functional interaction between FBXO11 and CDT2 is evolutionary conserved from worms to humans and plays an important role in regulating the timing of cell-cycle exit.
Subject(s)
Cell Cycle , F-Box Proteins/metabolism , Nuclear Proteins/metabolism , Protein-Arginine N-Methyltransferases/metabolism , Ubiquitin-Protein Ligases/metabolism , Amino Acid Sequence , Amino Acid Substitution , Cell Differentiation , Conserved Sequence , F-Box Proteins/genetics , Gene Knockdown Techniques , HEK293 Cells , HeLa Cells , Humans , Mutagenesis, Site-Directed , Nuclear Proteins/genetics , Phosphorylation , Protein Binding , Protein Processing, Post-Translational , Protein-Arginine N-Methyltransferases/genetics , RNA, Small Interfering/genetics , Ubiquitin-Protein Ligases/geneticsABSTRACT
FBH1 is a member of the UvrD family of DNA helicases and plays a crucial role in the response to DNA replication stress. In particular, upon DNA replication stress, FBH1 promotes double-strand breakage and activation of the DNA-PK and ATM signaling cascades in a helicase-dependent manner. In the present manuscript, we show that FBH1 is often deleted or mutated in melanoma cells, which results in their increased survival in response to replicative stress. Accordingly, FBH1 depletion promotes UV-mediated transformation of human melanocytes. Thus, FBH1 inactivation appears to contribute to oncogenic transformation by allowing survival of cells undergoing replicative stress due to external factors such as UV irradiation.
Subject(s)
DNA Helicases/metabolism , DNA-Binding Proteins/metabolism , Melanocytes/metabolism , Melanoma/metabolism , Cell Survival/drug effects , Cell Survival/radiation effects , Cell Transformation, Neoplastic/radiation effects , Cells, Cultured , DNA Breaks, Double-Stranded/drug effects , DNA Breaks, Double-Stranded/radiation effects , DNA Helicases/antagonists & inhibitors , DNA Helicases/genetics , DNA Replication , DNA-Binding Proteins/antagonists & inhibitors , DNA-Binding Proteins/genetics , Humans , Hydroxyurea/pharmacology , Melanocytes/cytology , Melanoma/pathology , Mutation , RNA Interference , RNA, Small Interfering/metabolism , Signal Transduction/drug effects , Ultraviolet RaysABSTRACT
Proper resolution of stalled replication forks is essential for genome stability. Purification of FBH1, a UvrD DNA helicase, identified a physical interaction with replication protein A (RPA), the major cellular single-stranded DNA (ssDNA)-binding protein complex. Compared with control cells, FBH1-depleted cells responded to replication stress with considerably fewer double-strand breaks (DSBs), a dramatic reduction in the activation of ATM and DNA-PK and phosphorylation of RPA2 and p53, and a significantly increased rate of survival. A minor decrease in ssDNA levels was also observed. All these phenotypes were rescued by wild-type FBH1, but not a FBH1 mutant lacking helicase activity. FBH1 depletion had no effect on other forms of genotoxic stress in which DSBs form by means that do not require ssDNA intermediates. In response to catastrophic genotoxic stress, apoptosis prevents the persistence and propagation of DNA lesions. Our findings show that FBH1 helicase activity is required for the efficient induction of DSBs and apoptosis specifically in response to DNA replication stress.
Subject(s)
Apoptosis , DNA Breaks, Double-Stranded , DNA Helicases/physiology , DNA Replication/physiology , DNA-Binding Proteins/physiology , Stress, Physiological , DNA Helicases/genetics , DNA Helicases/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Genomic Instability , HEK293 Cells , HeLa Cells , Humans , Hydroxyurea/pharmacology , Phosphorylation , Protein Structure, Tertiary , Replication Protein A/metabolism , Replication Protein A/physiology , S Phase , Ultraviolet RaysABSTRACT
F-box proteins are the substrate binding subunits of SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complexes. Using affinity purifications and mass spectrometry, we identified RRM2 (the ribonucleotide reductase family member 2) as an interactor of the F-box protein cyclin F. Ribonucleotide reductase (RNR) catalyzes the conversion of ribonucleotides to deoxyribonucleotides (dNTPs), which are necessary for both replicative and repair DNA synthesis. We found that, during G2, following CDK-mediated phosphorylation of Thr33, RRM2 is degraded via SCF(cyclin F) to maintain balanced dNTP pools and genome stability. After DNA damage, cyclin F is downregulated in an ATR-dependent manner to allow accumulation of RRM2. Defective elimination of cyclin F delays DNA repair and sensitizes cells to DNA damage, a phenotype that is reverted by expressing a nondegradable RRM2 mutant. In summary, we have identified a biochemical pathway that controls the abundance of dNTPs and ensures efficient DNA repair in response to genotoxic stress.