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Deubiquitinases (DUBs) are essential for the maintenance of protein homeostasis and assembly of proteins into functional complexes. Despite growing interest in DUBs biological functions, the roles of DUBs in regulating intestinal stem cells (ISCs) and gut homeostasis remain largely unknown. Here, we perform an in vivo RNAi screen through induced knock-down of DUBs expression in adult midgut ISCs and enteroblasts (EBs) to identify DUB regulators of intestinal homeostasis in Drosophila. We screen 43 DUBs and identify 8 DUBs that are required for ISCs homeostasis. Knocking-down of usp1, CG7857, usp5, rpn8, usp10 and csn5 decreases the number of ISCs/EBs, while knocking-down of CG4968 and usp8 increases the number of ISCs/EBs. Moreover, knock-down of usp1, CG4968, CG7857, or rpn8 in ISCs/EBs disrupts the intestinal barrier integrity and shortens the lifespan, indicating the requirement of these DUBs for the maintenance of gut homeostasis. Furthermore, we provide evidences that USP1 mediates ISC lineage differentiation via modulating the Notch signaling activity. Our study identifies, for the first time, the deubiquitinases required for the maintenance of intestinal homeostasis in Drosophila, and provide new insights into the functional links between the DUBs and intestinal homeostasis.
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Enzimas Desubiquitinantes , Proteínas de Drosophila , Homeostase , Intestinos , Interferência de RNA , Animais , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Enzimas Desubiquitinantes/metabolismo , Enzimas Desubiquitinantes/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Células-Tronco/metabolismo , Drosophila/genética , Drosophila/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Proteases Específicas de Ubiquitina/genéticaRESUMO
Poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) (PEDOT: PSS) is a promising material for organic thermoelectric (TE) applications. However, it is challenging to achieve PEDOT: PSS composites with stretchable, self-healable, and high TE performance. Furthermore, some existing self-healing TE materials employ toxic reagents, posing risks to human health and the environment. In this study, a novel intrinsically self-healable and wearable composite is developed by incorporating environmentally friendly, highly biocompatible, and biodegradable materials of polyvinyl alcohol (PVA) and citric acid (CA) into PEDOT: PSS. This results in the formation of double hydrogen bonding networks among CA, PVA, and PEDOT: PSS, inducing microstructure alignment and leading to simultaneous enhancements in both TE performance and stretchability. The resulting composites exhibit a high electrical conductivity and power factor of 259.3 ± 11.7 S·cm-1, 6.9 ± 0.4 µW·m-1·K-2, along with a tensile strain up to 68%. Furthermore, the composites display impressive self-healing ability, with 84% recovery in electrical conductivity and an 85% recovery in tensile strain. Additionally, the temperature and strain sensors based on the PEDOT: PSS/PVA/CA are prepared, which exhibit high resolution suitable for human-machine interaction and wearable devices. This work provides a reliable and robust solution for the development of environmentally friendly, self-healing and wearable TE thermoelectrics.
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Microbial degradation of tylosin (TYL) is a safe and environmentally friendly technology for remediating environmental pollution. Kurthia gibsonii (TYL-A1) and Klebsiella pneumonia (TYL-B2) were isolated from wastewater; degradation efficiency of the two strains combined was significantly greater than either alone and resulted in degradation products that were less toxic than TYL. With Polyvinyl alcohol (PVA)-sodium alginate (SA)-activated carbon (AC) used to form a bacterial immobilization carrier, the immobilized bacterial alliance reached 95.9% degradation efficiency in 1 d and could be reused for four cycles, with > 93% degradation efficiency per cycle. In a wastewater application, the immobilized bacterial alliance degraded 67.0% TYL in 9 d. There were significant advantages for the immobilized bacterial alliance at pH 5 or 9, with 20 or 40 g/L NaCl, or with 10 or 50 mg/L doxycycline. In summary, in this study, a bacterial consortium with TYL degradation ability was constructed using PVA-SA-AC as an immobilized carrier, and the application effect was evaluated on farm wastewater with a view to providing application guidance in environmental remediation.
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Biodegradação Ambiental , Células Imobilizadas , Álcool de Polivinil , Tilosina , Águas Residuárias , Águas Residuárias/química , Águas Residuárias/microbiologia , Álcool de Polivinil/química , Células Imobilizadas/metabolismo , Alginatos/química , Alginatos/metabolismo , Poluentes Químicos da Água/metabolismo , Klebsiella pneumoniae/metabolismo , Antibacterianos , Carvão Vegetal/químicaRESUMO
Plant pattern-recognition receptors perceive microorganism-associated molecular patterns to activate immune signalling1,2. Activation of the pattern-recognition receptor kinase CERK1 is essential for immunity, but tight inhibition of receptor kinases in the absence of pathogen is crucial to prevent autoimmunity3,4. Here we find that the U-box ubiquitin E3 ligase OsCIE1 acts as a molecular brake to inhibit OsCERK1 in rice. During homeostasis, OsCIE1 ubiquitinates OsCERK1, reducing its kinase activity. In the presence of the microorganism-associated molecular pattern chitin, active OsCERK1 phosphorylates OsCIE1 and blocks its E3 ligase activity, thus releasing the brake and promoting immunity. Phosphorylation of a serine within the U-box of OsCIE1 prevents its interaction with E2 ubiquitin-conjugating enzymes and serves as a phosphorylation switch. This phosphorylation site is conserved in E3 ligases from plants to animals. Our work identifies a ligand-released brake that enables dynamic immune regulation.
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Oryza , Imunidade Vegetal , Proteínas de Plantas , Ubiquitina , Animais , Quitina/metabolismo , Homeostase , Ligantes , Oryza/enzimologia , Oryza/imunologia , Oryza/metabolismo , Oryza/microbiologia , Fosforilação , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Plantas/imunologia , Proteínas de Plantas/metabolismo , Ubiquitina/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Fosfosserina/metabolismo , Sequência ConservadaRESUMO
The human cerebral cortex is folded into two fundamentally anatomical units: gyri and sulci. Previous studies have demonstrated the genetical, structural, and functional differences between gyri and sulci, providing a unique perspective for revealing the relationship among brain function, cognition, and behavior. While previous studies mainly focus on the functional differences between gyri and sulci under resting or task-evoked state, such characteristics under naturalistic stimulus (NS) which reflects real-world dynamic environments are largely unknown. To address this question, this study systematically investigates spatio-temporal functional connectivity (FC) characteristics between gyri and sulci under NS using a spatio-temporal graph convolutional network model. Based on the public Human Connectome Project dataset of 174 subjects with four different runs of both movie-watching NS and resting state 7T functional MRI data, we successfully identify unique FC features under NS, which are mainly involved in visual, auditory, emotional and cognitive control, and achieve high discriminative accuracy 93.06 % to resting state. Moreover, gyral regions as well as gyro-gyral connections consistently participate more as functional information exchange hubs than sulcal ones among these networks. This study provides novel insights into the functional brain mechanism under NS and lays a solid foundation for accurately mapping the brain anatomy-function relationship.
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Conectoma , Imageamento por Ressonância Magnética , Humanos , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiologia , EmoçõesRESUMO
Nitrogen (N) and phosphorus (P) are the most important macronutrients required for plant growth and development. To cope with the limited and uneven distribution of N and P in complicated soil environments, plants have evolved intricate molecular strategies to improve nutrient acquisition that involve adaptive root development, production of root exudates, and the assistance of microbes. Recently, great advances have been made in understanding the regulation of N and P uptake and utilization and how plants balance the direct uptake of nutrients from the soil with the nutrient acquisition from beneficial microbes such as arbuscular mycorrhiza. Here, we summarize the major advances in these areas and highlight plant responses to changes in nutrient availability in the external environment through local and systemic signals.
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A self-supporting composite electrode material with a unique three-dimensional structure was synthesized by in-situ growth of nanoscale NiMnLDH-Co(OH)2 on a nickel foam substrate via hydrothermal electrodeposition. The 3D layer of NiMnLDH-Co(OH)2 provided abundant reactive sites for electrochemical reactions, ensuring a solid and conductive skeleton for charge transfer and resulting in significant enhancement of electrochemical performance. The composite material showed a strong synergistic effect between the small nano-sheet Co(OH)2 and NiMnLDH, which promoted reaction kinetics, while the nickel foam substrate acted as a structural conductivity agent, stabilizer, and good conductive medium. The composite electrode showed impressive electrochemical performance, achieving a specific capacitance of 1870F g-1 at 1 A g-1 and retaining 87% capacitance after 3000 charge-discharge cycles, even at a high current density of 10 A g-1. Moreover, the resulting NiMnLDH-Co(OH)2//AC asymmetric supercapacitor (ASC) demonstrated remarkable specific energy of 58.2 Wh kg-1 at a specific power of 1200 W kg-1, along with outstanding cycle stability (89% capacitance retention after 5000 cycles at 10 A g-1). More importantly, DFT calculations reveal that NiMnLDH-Co(OH)2 facilitates charge transfer, accelerating surface redox reactions and increasing specific capacitance. This study presents a promising approach towards designing and developing advanced electrode materials for high-performance supercapacitors.
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Native mass spectrometry (MS) of proteins and protein assemblies reveals size and binding stoichiometry, but elucidating structures to understand their function is more challenging. Native top-down MS (nTDMS), i.e., fragmentation of the gas-phase protein, is conventionally used to derive sequence information, locate post-translational modifications (PTMs), and pinpoint ligand binding sites. nTDMS also endeavors to dissociate covalent bonds in a conformation-sensitive manner, such that information about higher-order structure can be inferred from the fragmentation pattern. However, the activation/dissociation method used can greatly affect the resulting information on protein higher-order structure. Methods such as electron capture/transfer dissociation (ECD and ETD, or ExD) and ultraviolet photodissociation (UVPD) can produce product ions that are sensitive to structural features of protein complexes. For multi-subunit complexes, a long-held belief is that collisionally activated dissociation (CAD) induces unfolding and release of a subunit, and thus is not useful for higher-order structure characterization. Here we show not only that sequence information can be obtained directly from CAD of native protein complexes but that the fragmentation pattern can deliver higher-order structural information about their gas- and solution-phase structures. Moreover, CAD-generated internal fragments (i.e., fragments containing neither N-/C-termini) reveal structural aspects of protein complexes.
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Projetos de Pesquisa , Espectrometria de MassasRESUMO
As an important medicinal plant, we still do not know the effect of exogenous hormones on absorption of elements and accumulation of secondary metabolites in Artemisia argyi leaves. In this work, we analyzed the difference in 21 elements absorbed by A. argyi leaves under three exogenous hormone (MeJA, SA and ABA) treatments, and also clarified the correlation between 21 elements and eight bioactive components. Different hormone treatments changed the absorption and enrichment of elements, and the composition also changed significantly. The contents of eight bioactive components changed significantly under different hormone treatments. When A. argyi was stimulated by exogenous hormones, the content of secondary metabolites was adjusted in the leaves through changes in the absorption and enrichment of elements. The widely untargeted metabolomic analysis further confirmed that ABA changes the metabolic direction of secondary metabolites in A. argyi leaves and stimulates the biosynthesis of multiple secondary metabolites including phenylpropanoids, flavonoids, terpenoids, alkaloids and others. These results provide a new perspective for the changes in element absorption and the mechanism of secondary metabolic components in A. argyi leaves under exogenous hormone treatments, and also deepen people's understanding of the interaction mechanism between medicinal plants and hormones.
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Most land plants associate with arbuscular mycorrhizal (AM) fungi to secure mineral nutrient acquisition, especially that of phosphorus. A phosphate starvation response (PHR)-centered network regulates AM symbiosis. Here, we identified 520 direct target genes for the rice transcription factor OsPHR1/2/3 during AM symbiosis using transcriptome deep sequencing and DNA affinity purification sequencing. These genes were involved in strigolactone biosynthesis, transcriptional reprogramming, and bidirectional nutrient exchange. Moreover, we identified the receptor-like kinase, Arbuscule Development Kinase 1 (OsADK1), as a new target of OsPHR1/2/3. Electrophoretic mobility shift assays and transactivation assays showed that OsPHR2 can bind directly to the P1BS elements within the OsADK1 promoter to activate its transcription. OsADK1 appeared to be required for mycorrhizal colonization and arbuscule development. In addition, hydroponic experiments suggested that OsADK1 may be involved in plant Pi starvation responses. Our findings validate a role for OsPHR1/2/3 as master regulators of mycorrhizal-related genes involved in various stages of symbiosis, and uncover a new RLK involved in AM symbiosis and plant Pi starvation responses.
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Micorrizas , Micorrizas/fisiologia , Simbiose/fisiologia , Fosfatos/metabolismo , Regulação da Expressão Gênica de Plantas , Raízes de Plantas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
The cerebral cortex is folded as gyri and sulci, which provide the foundation to unveil anatomo-functional relationship of brain. Previous studies have extensively demonstrated that gyri and sulci exhibit intrinsic functional difference, which is further supported by morphological, genetic, and structural evidences. Therefore, systematically investigating the gyro-sulcal (G-S) functional difference can help deeply understand the functional mechanism of brain. By integrating functional magnetic resonance imaging (fMRI) with advanced deep learning models, recent studies have unveiled the temporal difference in functional activity between gyri and sulci. However, the potential difference of functional connectivity, which represents functional dependency between gyri and sulci, is much unknown. Moreover, the regularity and variability of the G-S functional connectivity difference across multiple task domains remains to be explored. To address the two concerns, this study developed new anatomy-guided spatio-temporal graph convolutional networks (AG-STGCNs) to investigate the regularity and variability of functional connectivity differences between gyri and sulci across multiple task domains. Based on 830 subjects with seven different task-based and one resting state fMRI (rs-fMRI) datasets from the public Human Connectome Project (HCP), we consistently found that there are significant differences of functional connectivity between gyral and sulcal regions within task domains compared with resting state (RS). Furthermore, there is considerable variability of such functional connectivity and information flow between gyri and sulci across different task domains, which are correlated with individual cognitive behaviors. Our study helps better understand the functional segregation of gyri and sulci within task domains as well as the anatomo-functional-behavioral relationship of the human brain.
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Simplified electrochemical atom transfer radical polymerization (seATRP) using CuII-N-propyl pyridineimine complexes (CuII(NPPI)2) is reported for the first time. In aqueous solution, using oligo(ethylene glycol) methyl ether methacrylate (OEGMA), standard electrolysis conditions yield POEGMA with good control over molecular weight distribution (D m < 1.35). Interestingly, the polymerizations are not under complete electrochemical control, as monomer conversion continues when electrolysis is halted. Alternatively, it is shown that the extent and rate of polymerization depends upon an initial period of electrolysis. Thus, it is proposed that seATRP using CuII(NPPI)2 follows an electrochemically-triggered, rather than electrochemically mediated, ATRP mechanism, which distinguishes them from other CuIIL complexes that have been previously reported in the literature.
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Arbuscular mycorrhizal (AM) fungi form a mutual association with the majority of land plants, including most angiosperms of the dicotyledon and monocotyledon lineages. The symbiosis is based upon bidirectional nutrient exchange between the host and symbiont that occurs between inner cortical cells of the root and branched AM hyphae called arbuscules that develop within these cells. Lipid transport and its regulation during the symbiosis have been intensively investigated in dicotyledon plants, especially legumes. Here, we characterize OsRAM2 and OsRAM2L, homologs of Medicago truncatula RAM2, and found that plants defective in OsRAM2 were unable to be colonized by AM fungi and showed impaired colonization by Magnaporthe oryzae. The induction of OsRAM2 and OsRAM2L is dependent on OsRAM1 and the common symbiosis signaling pathway pathway genes CCaMK and CYCLOPS, while overexpression of OsRAM1 results in increased expression of OsRAM2 and OsRAM2L. Collectively, our data show that the function and regulation of OsRAM2 is conserved in monocot and dicot plants and reveals that, similar to mutualistic fungi, pathogenic fungi have recruited RAM2-mediated fatty acid biosynthesis to facilitate invasion.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.
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Medicago truncatula , Micorrizas , Oryza , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica de Plantas , Medicago truncatula/microbiologia , Micorrizas/fisiologia , Oryza/genética , Raízes de Plantas/microbiologia , Simbiose/genéticaRESUMO
Pasteurella multocida is one of the primary pathogens of bovine respiratory disease (BRD), and causes huge losses in the cattle industry. The Pm3 strain was a natural isolate, which is a strong form of pathogen and is sensitive to fluoroquinolones antibiotics. A high fluoroquinolone resistant strain, Pm64 (MIC = 64 µg/mL), was formed after continuous induction with subinhibitory concentration (1/2 MIC) of enrofloxacin, with the enhanced growth characteristics and large attenuation of pathogenicity in mice. This study reports the whole genome sequence and the transcription profile by RNA-Seq of strain Pm3/Pm64. The results showed an ineffective difference between the two strains at the genome level. However, 32 genes could be recognized in the gene islands (GIs) of Pm64, in which 24 genes were added and 8 genes were lost. Those genes are involved in DNA binding, trehalose metabolism, material transportation, capsule synthesis, prophage, amino acid metabolism, and other functions. In Pm3 strain, 558 up-regulated and 568 down-regulated genes were found compared to Pm64 strain, from which 20 virulence factor-related differentially expressed genes (DEGs) were screened. Mainly differentially transcribed genes were associated with capsular polysaccharide (CPS), lipopolysaccharide (LPS), lipooligosaccharide (LOS). Iron utilization, and biofilm composition. We speculated that the main mechanism of virulence attenuation after the formation of resistance of Pm64 comes from the change of the expression profile of these genes. This report elucidated the toxicity targets of P. multocida serogroup A which provide fundamental information toward the understanding of the pathogenic mechanism and to decreasing antimicrobial drugs resistance.
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OBJECTIVES: Intensive care audits point to family refusal as a major barrier to organ donation. In this study, we sought to understand refusal by accounting for the decision-maker's mindset. This focused on: (1) how decisions compare when made on behalf of a relative (vs the self); and (2) confidence in decisions made for family members. DESIGN: Cross-sectional survey in Singapore. SETTING: Participants were recruited from community settings via door-to-door sampling and community eateries. PARTICIPANTS: 973 adults who qualified as organ donors in Singapore. RESULTS: Although 68.1% of participants were willing to donate their own organs, only 51.8% were willing to donate a relative's organs. Using machine learning, we found that consistency was predicted by: (1) religion, and (2) fears about organ donation. Conversely, participants who were willing to donate their own organs but not their relative's were less driven by these factors, and may instead have resorted to heuristics in decision-making. Finally, we observed how individuals were overconfident in their decision-making abilities: although 78% had never discussed organ donation with their relatives, the large majority expressed high confidence that they would respect their relatives' wishes on death. CONCLUSIONS: These findings underscore the distinct psychological processes involved when donation decisions are made for family members. Amidst a global shortage of organ donors, addressing the decision-maker's mindset (eg, overconfidence, the use of heuristics) may be key to actualizing potential donors identified in intensive care units.
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Transplante de Órgãos , Obtenção de Tecidos e Órgãos , Adulto , Estudos Transversais , Tomada de Decisões , Família , Humanos , Doadores de TecidosRESUMO
To secure phosphorus (P) from soil, most land plants use a direct phosphate uptake pathway via root hairs and epidermis and an indirect phosphate uptake pathway via mycorrhizal symbiosis. The interaction between these two pathways is unclear. Here, we mapped a network between transcription factors and mycorrhizal symbiosis-related genes using Y1H. Intriguingly, this gene regulatory network is governed by the conserved P-sensing pathway, centered on phosphate starvation response (PHR) transcription factors. PHRs are required for mycorrhizal symbiosis and regulate symbiosis-related genes via the P1BS motif. SPX-domain proteins suppress OsPHR2-mediated induction of symbiosis-related genes and inhibit mycorrhizal infection. In contrast, plants overexpressing OsPHR2 show improved mycorrhizal infection and are partially resistant to P-mediated inhibition of symbiosis. Functional analyses of network nodes revealed co-regulation of hormonal signaling and mycorrhizal symbiosis. This network deciphers extensive regulation of mycorrhizal symbiosis by endogenous and exogenous signals and highlights co-option of the P-sensing pathway for mycorrhizal symbiosis.
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Redes Reguladoras de Genes , Micorrizas/genética , Micorrizas/fisiologia , Fosfatos/deficiência , Simbiose/genética , Simbiose/fisiologia , Sequência de Bases , Regulação da Expressão Gênica de Plantas , Mutação/genética , Oryza/genética , Oryza/microbiologia , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regiões Promotoras Genéticas/genética , Saccharomyces cerevisiae/metabolismo , Técnicas do Sistema de Duplo-HíbridoRESUMO
A simplified 'plug-and-play' approach to aqueous electrochemical atom transfer radical polymerization (eATRP) has been developed. Well-controlled polymerization of PEGA480 (Dm = 1.17-1.31) is reported under potentiostatic (3-electrodes, undivided cell) and galvanostatic (2-electrodes, 6-steps) conditions.
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Inactivating mutations affecting key mismatch repair (MMR) components lead to microsatellite instability (MSI) and cancer. However, a number of patients with MSI-tumors do not present alterations in classical MMR genes. Here we discovered that specific missense mutations in the MutL homolog MLH2, which is dispensable for MMR, confer a dominant mutator phenotype in S. cerevisiae. MLH2 mutations elevated frameshift mutation rates, and caused accumulation of long-lasting nuclear MMR foci. Both aspects of this phenotype were suppressed by mutations predicted to prevent the binding of Mlh2 to DNA. Genetic analysis revealed that mlh2 dominant mutations interfere with both Exonuclease 1 (Exo1)-dependent and Exo1-independent MMR. Lastly, we demonstrate that a homolog mutation in human hPMS1 results in a dominant mutator phenotype. Our data support a model in which yeast Mlh1-Mlh2 or hMLH1-hPMS1 mutant complexes act as roadblocks on DNA preventing MMR, unraveling a novel mechanism that can account for MSI in human cancer.
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Reparo de Erro de Pareamento de DNA/genética , Proteínas MutL/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Dano ao DNA , Deleção de Genes , Humanos , Proteínas MutL/genética , Mutação , Proteínas de Neoplasias/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Técnicas do Sistema de Duplo-HíbridoRESUMO
BACKGROUND: Historically, brain death legislation was adopted in Asia at a much later stage than it was in the West, with heated public debates surrounding these laws. In this study, we investigated whether the poor acceptance of brain death continues to the present day, focusing on the following: (1) what the Asian public understands brain death to be; (2) how views toward brain death are compared with those of cardiac death; and (3) the extent to which brain death perception contributes to the low rate of deceased organ donation that has been observed amongst Asians. METHODS: Using a door-to-door sampling strategy, we recruited 622 residents in Singapore between September 2016 and July 2017. RESULTS: Our results suggest that resistance toward brain death persists, with the majority of respondents equating this as a bleak outcome but not as death. Correspondingly, they considered cardiac death a better indicator of death and were more fearful of being alive during organ donation. In turn, these views predicted a decreased willingness to donate either their own or their family members' organs. CONCLUSIONS: Taken together, our results suggest that views of brain death continue to hamper organ donation, and are seemingly resistant to both time and legislation.
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Morte Encefálica , Obtenção de Tecidos e Órgãos , Ásia , Estudos Transversais , Parada Cardíaca , Humanos , Inquéritos e QuestionáriosRESUMO
The balance and the overall concentration of intracellular deoxyribonucleoside triphosphates (dNTPs) are important determinants of faithful DNA replication. Despite the established fact that changes in dNTP pools negatively influence DNA replication fidelity, it is not clear why certain dNTP pool alterations are more mutagenic than others. As intracellular dNTP pools are mainly controlled by ribonucleotide reductase (RNR), and given the limited number of eukaryotic RNR mutations characterized so far, we screened for RNR1 mutations causing mutator phenotypes in Saccharomyces cerevisiae. We identified 24 rnr1 mutant alleles resulting in diverse mutator phenotypes linked in most cases to imbalanced dNTPs. Among the identified rnr1 alleles the strongest mutators presented a dNTP imbalance in which three out of the four dNTPs were elevated (dCTP, dTTP and dGTP), particularly if dGTP levels were highly increased. These rnr1 alleles caused growth defects/lethality in DNA replication fidelity-compromised backgrounds, and caused strong mutator phenotypes even in the presence of functional DNA polymerases and mismatch repair. In summary, this study pinpoints key residues that contribute to allosteric regulation of RNR's overall activity or substrate specificity. We propose a model that distinguishes between different dNTP pool alterations and provides a mechanistic explanation why certain dNTP imbalances are particularly detrimental.