更新于：2024-11-01

RNR x RNR1

更新于：2024-11-01

基本信息

关联

项与 RNR x RNR1 相关的药物

LOR-2501

靶点

RNR1 x 核糖核苷酸还原酶复合体

作用机制

RNR抑制剂 [+1]

在研机构-

原研机构

Aptose Biosciences, Inc.

在研适应症-

非在研适应症

肾肿瘤 [+2]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 RNR x RNR1 相关的临床结果

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100 项与 RNR x RNR1 相关的转化医学

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0 项与 RNR x RNR1 相关的专利（医药）

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项与 RNR x RNR1 相关的文献（医药）

2023-12-01·BioMetals

Iron necessity for chlamydospore germination in Fusarium oxysporum f. sp. cubense TR4

Article

作者: Rasche, Frank ; Were, Evans ; Viljoen, Altus

AbstractFusarium wilt disease of banana, caused by the notorious soil-borne pathogen Fusarium oxysporum f. sp. cubense Tropical Race 4 (Foc TR4), is extremely difficult to manage. Manipulation of soil pH or application of synthetic iron chelators can suppress the disease through iron starvation, which inhibits the germination of pathogen propagules called chlamydospores. However, the effect of iron starvation on chlamydospore germination is largely unknown. In this study, scanning electron microscopy was used to assemble the developmental sequence of chlamydospore germination and to assess the effect of iron starvation and pH in vitro. Germination occurs in three distinct phenotypic transitions (swelling, polarized growth, outgrowth). Outgrowth, characterized by formation of a single protrusion (germ tube), occurred at 2 to 3 h, and a maximum value of 69.3% to 76.7% outgrowth was observed at 8 to 10 h after germination induction. Germination exhibited plasticity with pH as over 60% of the chlamydospores formed a germ tube between pH 3 and pH 11. Iron-starved chlamydospores exhibited polarized-growth arrest, characterized by the inability to form a germ tube. Gene expression analysis of rnr1 and rnr2, which encode the iron-dependent enzyme ribonucleotide reductase, showed that rnr2 was upregulated (p < 0.0001) in iron-starved chlamydospores compared to the control. Collectively, these findings suggest that iron and extracellular pH are crucial for chlamydospore germination in Foc TR4. Moreover, inhibition of germination by iron starvation may be linked to a different mechanism, rather than repression of the function of ribonucleotide reductase, the enzyme that controls growth by regulation of DNA synthesis.

2023-10-01·Plant science : an international journal of experimental plant biology

Analysis of the Arabidopsis venosa4-0 mutant supports the role of VENOSA4 in dNTP metabolism.

Article

作者: Quesada, Víctor ; Sarmiento-Mañús, Raquel ; Barrajón-Catalán, Enrique ; Ponce, María Rosa ; Hannah, Matthew A ; Micol, Vicente ; Fontcuberta-Cervera, Sara ; Álvarez-Martínez, Francisco Javier ; González-Bayón, Rebeca ; Micol, José Luis

Human Sterile alpha motif and histidine-aspartate domain containing protein 1 (SAMHD1) functions as a dNTPase to maintain dNTP pool balance. In eukaryotes, the limiting step in de novo dNTP biosynthesis is catalyzed by RIBONUCLEOTIDE REDUCTASE (RNR). In Arabidopsis, the RNR1 subunit of RNR is encoded by CRINKLED LEAVES 8 (CLS8), and RNR2 by three paralogous genes, including TSO MEANING 'UGLY' IN CHINESE 2 (TSO2). In plants, DIFFERENTIAL DEVELOPMENT OF VASCULAR ASSOCIATED CELLS 1 (DOV1) catalyzes the first step of the de novo biosynthesis of purines. Here, to explore the role of VENOSA4 (VEN4), the most likely Arabidopsis ortholog of human SAMHD1, we studied the ven4-0 point mutation, whose leaf phenotype was stronger than those of its insertional alleles. Structural predictions suggested that the E249L substitution in the mutated VEN4-0 protein rigidifies its 3D structure. The morphological phenotypes of the ven4, cls8, and dov1 single mutants were similar, and those of the ven4 tso2 and ven4 dov1 double mutants were synergistic. The ven4-0 mutant had reduced levels of four amino acids related to dNTP biosynthesis, including glutamine and glycine, which are precursors in the de novo purine biosynthesis. Our results reveal high functional conservation between VEN4 and SAMHD1 in dNTP metabolism.

2022-07-30·Genetics

Complex mutation profiles in mismatch repair and ribonucleotide reductase mutants reveal novel repair substrate specificity of MutS homolog (MSH) complexes

Article

作者: Brown, Grant W ; Lamb, Natalie A ; Surtees, Jennifer A ; Bard, Jonathan E ; Loll-Krippleber, Raphael

AbstractDetermining mutation signatures is standard for understanding the etiology of human tumors and informing cancer treatment. Multiple determinants of DNA replication fidelity prevent mutagenesis that leads to carcinogenesis, including the regulation of free deoxyribonucleoside triphosphate pools by ribonucleotide reductase and repair of replication errors by the mismatch repair system. We identified genetic interactions between rnr1 alleles that skew and/or elevate deoxyribonucleoside triphosphate levels and mismatch repair gene deletions. These defects indicate that the rnr1 alleles lead to increased mutation loads that are normally acted upon by mismatch repair. We then utilized a targeted deep-sequencing approach to determine mutational profiles associated with mismatch repair pathway defects. By combining rnr1 and msh mutations to alter and/or increase deoxyribonucleoside triphosphate levels and alter the mutational load, we uncovered previously unreported specificities of Msh2–Msh3 and Msh2–Msh6. Msh2–Msh3 is uniquely able to direct the repair of G/C single-base deletions in GC runs, while Msh2–Msh6 specifically directs the repair of substitutions that occur at G/C dinucleotides. We also identified broader sequence contexts that influence variant profiles in different genetic backgrounds. Finally, we observed that the mutation profiles in double mutants were not necessarily an additive relationship of mutation profiles in single mutants. Our results have implications for interpreting mutation signatures from human tumors, particularly when mismatch repair is defective.