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Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability.
Nat Commun
March 2024
Department of Urology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
Tumor cells must rewire nucleotide synthesis to satisfy the demands of unbridled proliferation. Meanwhile, they exhibit augmented reactive oxygen species (ROS) production which paradoxically damages DNA and free deoxy-ribonucleoside triphosphates (dNTPs). How these metabolic processes are integrated to fuel tumorigenesis remains to be investigated.
View Article and Find Full Text PDFMetabolic clogging of mannose triggers dNTP loss and genomic instability in human cancer cells.
Elife
July 2023
Department of Glyco-Oncology and Medical Biochemistry, Research Institute, Osaka International Cancer Institute, Osaka, Japan.
Mannose has anticancer activity that inhibits cell proliferation and enhances the efficacy of chemotherapy. How mannose exerts its anticancer activity, however, remains poorly understood. Here, using genetically engineered human cancer cells that permit the precise control of mannose metabolic flux, we demonstrate that the large influx of mannose exceeding its metabolic capacity induced metabolic remodeling, leading to the generation of slow-cycling cells with limited deoxyribonucleoside triphosphates (dNTPs).
View Article and Find Full Text PDFHuman PrimPol Discrimination against Dideoxynucleotides during Primer Synthesis.
Genes (Basel)
September 2021
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), c/Nicolás Cabrera 1, Cantoblanco, 28049 Madrid, Spain.
PrimPol is required to re-prime DNA replication at both nucleus and mitochondria, thus facilitating fork progression during replicative stress. ddC is a chain-terminating nucleotide that has been widely used to block mitochondrial DNA replication because it is efficiently incorporated by the replicative polymerase Polγ. Here, we show that human PrimPol discriminates against dideoxynucleotides (ddNTP) when elongating a primer across 8oxoG lesions in the template, but also when starting synthesis of DNA primers, and especially when selecting the 3'nucleotide of the initial dimer.
View Article and Find Full Text PDFA Convenient and Sensitive Method for Deoxynucleoside Triphosphate Quantification by the Combination of Rolling Circle Amplification and Quantitative Polymerase Chain Reaction.
Anal Chem
October 2021
Institute of Molecular Medicine, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei 100, Taiwan, R.O.C.
Measurement of four dNTP pools is important for investigating metabolism, genome stability, and drug action. In this report, we developed a two-step method for quantitating dNTPs by the combination of rolling circle amplification (RCA) and quantitative polymerase chain reaction (qPCR). We used CircLigase to generate a single-strand DNA in circular monomeric configuration, which was then used for the first step of RCA reaction that contained three dNTPs in excess for quantification of one dNTP at limiting levels.
View Article and Find Full Text PDFExcess dNTPs Trigger Oscillatory Surface Flow in the Early Drosophila Embryo.
Biophys J
May 2020
Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey; Lewis Sigler Institute of Integrative Genomics, Princeton University, Princeton, New Jersey; Department of Molecular Biology, Princeton University, Princeton, New Jersey; Center for Computational Biology, Flatiron Institute, New York, New York. Electronic address:
During the first 2 hours of Drosophila development, precisely orchestrated nuclear cleavages, cytoskeletal rearrangements, and directed membrane growth lead to the formation of an epithelial sheet around the yolk. The newly formed epithelium remains relatively quiescent during the next hour as it is patterned by maternal inductive signals and zygotic gene products. We discovered that this mechanically quiet period is disrupted in embryos with high levels of dNTPs, which have been recently shown to cause abnormally fast nuclear cleavages and interfere with zygotic transcription.
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