Disease relevance of uracil

• Our results suggest that dUTP can be incorporated in place of dTTP into polyoma DNA, and that polyoma-infected nuclei, similar to E. coli (Tye et al., 1977), contain an excision-repair system which by removal of uracil causes strand breakage and under certain circumstances may contribute to the formation of Okazaki fragments [1].
• Uracil-DNA glycosylase inhibitor (Ugi) is a B. subtilis bacteriophage protein that protects the uracil-containing phage DNA by irreversibly inhibiting the key DNA repair enzyme uracil-DNA glycosylase (UDG) [2].
• Uracil in DNA in megaloblastic anemia [3].
• A single injection of the uracil auxotroph into BALB/c mice induces long-term protective immunity to toxoplasmosis [4].
• Uracil mustard in the treatment of thrombocytosis [5].

High impact information on uracil

• Recently, a biochemically distinct family of DNA repair enzymes has been identified, which excises both uracil and thymine, but only from mispairs with guanine [6].
• Uracil is removed in a base-excision repair pathway by uracil DNA-glycosylase (UDG), which excises uracil from both single- and double-stranded DNA [6].
• The high levels of dUTPase as well as the presence of RNA primers on most nascent DNA pieces (Tseng and Goulian, 1977) suggest that repair of uracil-containing DNA does not contribute to the generation of the small, nascent DNA pieces found during DNA synthesis in this in vitro system [7].
• Addition of uracil, a known inhibitor of the enzyme uracil-DNA glycosidase (Lindahl et al., 1977), increased total synthesis and shifted the incorporation to longer progeny strands [1].
• We have examined the virulence of T. gondii mutants that lack carbamoyl phosphate synthetase II (uracil auxotrophs) to determine whether de novo pyrimidine biosynthesis is required in vivo [4].

Chemical compound and disease context of uracil

• T4 bacteriophage DNA containing as much as 30% of its thymine replaced by uracil can be synthesised in Escherichia coli deficient in both dUTPase and uracil--DNA glycosidase [8].
• The enzyme dUTPase catalyses the hydrolysis of dUTP and maintains a low intracellular concentration of dUTP so that uracil cannot be incorporated into DNA. dUTPase from Escherichia coli is strictly specific for its dUTP substrate, the active site discriminating between nucleotides with respect to the sugar moiety as well as the pyrimidine base [9].
• Luciferase gene expression analysis with DNA templates containing uracil or 8-oxoguanine, placed at a defined position, indicated that in nondividing Escherichia coli cells, efficient mutagenic lesion bypass does occur in vivo during transcription [10].
• Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer: a randomised trial. Gastric Cancer Surgical Study Group [11].
• Highly expressed mRNAs in Escherichia coli favor codons terminating in cytosine rather than uracil when both codons are read by a single tRNA with an anticodon beginning with guanine [12].

Biological context of uracil

• Mispairs in DNA of guanine with uracil and thymine can arise as a result of deamination of cytosine and 5-methylcytosine, respectively [13].
• But selection of Ura+ prototrophs from a Ura- strain carrying URA3 on a plasmid in its mitochondria enabled us to detect plasmid movement to the nucleus [14].
• A covalent adduct between the uracil ring and the active site of an aminoacyl tRNA synthetase [15].
• We have further identified two bacterial proteins with strong sequence homology to this core and shown that the homologue from Escherichia coli (dsUDG) can remove uracil from G/U mispairs [13].
• All externally, suppressible frameshift mutations occur in glycine and proline codons to produce the four-base codons GGGU (U, uracil), GGGG, and CCCU [16].

Anatomical context of uracil

• Extracts from these cell lines were found to be defective in uracil-initiated base-excision repair [17].
• Together with the finding that nuclear UNG expression was induced in activated B cells, these data support a model of CSR and SHM in which AID deaminates cytosine into uracil in targeted DNA (immunoglobulin switch or variable regions), followed by uracil removal by UNG [18].
• However, when exposed to a nitric oxide donor, Ung(-/-) fibroblasts show an increase in the uracil/cytosine ratio in the genome and augmented cell death [19].
• In addition to its role in selective protein degradation, the conjugation of ubiquitin to proteins has also been implicated in the internalization of plasma membrane proteins, including the alpha-factor receptor Ste2p, uracil permease Fur4p, epithelial sodium channel ENaC and the growth hormone receptor (GHR) [20].
• Cell lines inoculated with "convalescent" cerebrospinal fluid showed slightly increased uracil uptake, slightly decreased uptake ratios, and persistent FA staining of approximately 5% of cells, indicating incomplete clearance of M. pneumoniae [21].

Associations of uracil with other chemical compounds

• Cytosine deamination produces mismatched uracil (U), which can be removed by uracil glycosylase, whereas m5C deamination generates a G x T mispair that cannot be processed by this enzyme [22].
• We show here that in bacteria which lack uracil-DNA glycosylase (Ung-) and cannot excise uracil residues from DNA, the rate of spontaneous transition at cytosine residues is raised to the hotspot rate at 5-methylcytosine residues [23].
• In vitro evolution was used to obtain ligase ribozymes composed of only 2,6-diaminopurine and uracil nucleotides, which catalyse the template-directed joining of two RNA molecules, one bearing a 5'-triphosphate and the other a 3'-hydroxyl [24].
• Irradiation of solutions at pH 7 to pH 8.5 of orotic acid, orotidine, and orotidine 5'-phosphate with light at 254 nanometers yields the corresponding uracil derivative via the singlet excited state [25].
• Exogenous uridine and cytidine are mostly converted to uracil by uridine phosphorylase and cytidine deaminase in T. foetus prior to incorporation [26].
• Cardiomyocytes do not need to be 'primed' by uracil nucleotides to become insensitive to adenine nucleotides-induced death, suggesting the existence of a possible 'therapeutic' window for uracil nucleotides-mediated protection [27].

Gene context of uracil

• Therefore, HIV-1 prevents incorporation of dUTP in viral cDNA by UNG2-mediated uracil excision followed by a dNTP-dependent, reverse transcriptase-mediated endonucleolytic cleavage and finally by strand-displacement polymerization [28].
• Ung knockout mice display no increase in mutation frequency due to a second UDG activity, SMUG1, which is specialized for antimutational uracil excision in mammalian cells [29].
• Moreover, the UNG mutations lead to increased accumulation of genomic uracil [30].
• Analyses with isogenic uracil-DNA-glycosylase (UNG1) deficient or proficient strains indicate that in the absence of dUTPase, cell death results from the incorporation of uracil into DNA and the attempted repair of this damage by UNG1-mediated excision repair [31].
• The Ung and Smug1 enzymes excise uracil from DNA to effect repair in mammalian cells, and gene-targeted Ung(-/-) mice exhibit a moderate increase in genome-wide spontaneous mutagenesis [32].

Analytical, diagnostic and therapeutic context of uracil

• Results from high performance liquid chromatography of pyrimidine and pyrimidine nucleoside pulse-labeled nucleotide pools and enzyme assays suggest that the parasite satisfies its pyrimidine nucleotide needs predominantly through salvage of uracil by a cytoplasmic uracil phosphoribosyltransferase [33].
• Biosynthetic labeling of RNA with uracil phosphoribosyltransferase allows cell-specific microarray analysis of mRNA synthesis and decay [34].
• Single-primer extension PCR and enzymatic digestion with uracil-N-glycosylase confirm that each of these groups of transitions result from a single event, the deamination of adenine to hypoxanthine, and cytosine to uracil, respectively [35].
• These findings provide a biochemical rationale that may be useful in designing clinical protocols that use 5-fluorinated uracil analogs [36].
• Recent studies using anion exclusion chromatography have suggested that uracil is misincorporated into the DNA of patients with megaloblastic anemia to levels detectable by nonradioactive methods [37].

References