Enigmatic 5-hydroxymethyluracil: Oxidatively modified base, epigenetic mark or both?

A variety of endogenous and exogenous agents can induce DNA damage and lead to genomic instability. Reactive oxygen species (ROS), an important class of DNA damaging agents, are constantly generated in cells as a consequence of endogenous metabolism, infection/inflammation, and/or exposure to environmental toxicants. A wide array of DNA lesions can be induced by ROS directly, including single-nucleobase lesions, tandem lesions, and hypochlorous acid (HOCl)/hypobromous acid (HOBr)-derived DNA adducts. ROS can also lead to lipid peroxidation, whose byproducts can also react with DNA to produce exocyclic DNA lesions. A combination of bioanalytical chemistry, synthetic organic chemistry, and molecular biology approaches have provided significant insights into the occurrence, repair, and biological consequences of oxidatively induced DNA lesions. The involvement of these lesions in the etiology of human diseases and aging was also investigated in the past several decades, suggesting that the oxidatively induced DNA adducts, especially bulky DNA lesions, may serve as biomarkers for exploring the role of oxidative stress in human diseases. The continuing development and improvement of LC-MS/MS coupled with the stable isotope-dilution method for DNA adduct quantification will further promote research about the clinical implications and diagnostic applications of oxidatively induced DNA adducts.

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“…67,223 The occurrence, repair, and biological consequences of 5-hmdU were previously reviewed. 189,224 …”

Section: Repair and Biological Consequences Of Oxidative Stress-inmentioning

confidence: 99%

Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage

Cui

Niedernhofer

et al. 2016

Chem. Res. Toxicol.

150

135

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“…Studies have detected 5hmU in mammalian DNA and its role as an epigenetic regulator is currently an active area of investigation. 2 Thymidine replacement by the unnatural thymidine analog, 5-bromouridine, has been previously studied by Hanawalt and coworkers 26 and more recently, Mutzel and coworkers studied thymidine replacement by 5-chlorouridine. 27 Here we focused on 5hmU incorporation since a complete replacement of thymidine with 5hmU is observed in the SPO1 bacillus phage genome.…”

mentioning

confidence: 99%

Replacement of Thymidine by a Modified Base in the Escherichia coli Genome

Mehta

Reed

et al. 2016

J. Am. Chem. Soc.

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Prokaryotic and eukaryotic genomic DNA is comprised of the four building blocks A, G, C and T. We have begun to explore the consequences of replacing a large fraction or all of a nucleoside in genomic DNA with a modified nucleoside. As a first step we have investigated the possibility of replacement of T by 2′-deoxy-5-(hydroxymethyl)uridine (5hmU) in the genomic DNA of E. coli. Metabolic engineering with phage genes followed by random mutagenesis enabled us to achieve approximately 75% replacement of T by 5hmU in the E. coli genome and in plasmids.

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“…5-methylcytosine (5-mC) is a good epigenetic marker, which plays an important role in cell differentiation and cancer (Lian et al, 2012). Further oxidation of 5-mC can lead to generate 5-hydroxymethylcytosine (5-hmC), 5carboxycytosine (5-caC) and 5-formylcytosine (5-fC) (Guo et al, 2013;Olinski, Starczak, & Gackowski, 2016). DNA methyltransferases are responsible for the methylation of the C-5 position of cytosine whereas ten-eleven translocation family enzymes cause oxidation of 5-mC to form 5-hmC, 5-caC and 5-fC (Rasmussen & Helin, 2016;Scourzic, Mouly, & Bernard, 2015).…”

Section: Techniques Used To Analyze Gene and Protein Expressionmentioning

confidence: 99%

In vitro assays and techniques utilized in anticancer drug discovery

Ediriweera

Tennekoon

Samarakoon

2018

J of Applied Toxicology

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Development of a cancer is a multistep process and six major hallmarks of cancer that are known to control malignant transformation have been described. Anticancer drug development is a tedious process, requiring a number of in vitro, in vivo and clinical studies. In vitro assays provide an initial platform for cancer drug discovery approaches. A wide range of in vitro assays/techniques have been developed to evaluate each hallmark feature of cancer and selection of a particular in vitro assay or technique mainly depends on the specific research question (s) to be examined. In the present review, we have described some commonly utilized in vitro assays and techniques used to examine cell viability/proliferation, apoptosis, cellular senescence, invasion and migration, oxidative stress and antioxidant effects, gene and protein expression, angiogenesis and genomic alterations in cancer drug discovery. Additionally, uses of modern techniques such as high throughput screening, high content screening and reporter gene assays in cancer drug discovery have also been described.

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Enigmatic 5-hydroxymethyluracil: Oxidatively modified base, epigenetic mark or both?

Cited by 77 publications

References 61 publications

Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage

Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage

Replacement of Thymidine by a Modified Base in the Escherichia coli Genome

In vitro assays and techniques utilized in anticancer drug discovery

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