Disease relevance of Ung

• Mutation frequencies and AID activation state in B-cell lymphomas from Ung-deficient mice [1].
• Lymphoid hyperplasia occurs very early in otherwise healthy Ung-deficient mice, observed as a significant increase of splenic B-cells [2].
• Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase [3].
• It does release uracil from the uracil-containing DNA of phage PBS2, but this activity is less than 2% of the predominant uracil DNA glycosylase activity of the cell, which is separated by phosphocellulose chromatography [4].
• Importance of uracil DNA glycosylase in Pseudomonas aeruginosa and Mycobacterium smegmatis, G+C-rich bacteria, in mutation prevention, tolerance to acidified nitrite, and endurance in mouse macrophages [5].

High impact information on Ung

• Uracil-DNA glycosylase (UNG)-deficient mice reveal a primary role of the enzyme during DNA replication [6].
• In the absence of uracil-DNA glycosylase (UNG) and the homologue of bacterial MutS (MSH)-2 mismatch recognition protein, the resultant U:G lesions are not processed into switching events but are fixed by replication allowing sites of AID-catalyzed deamination to be identified by the resulting C-->T mutations [7].
• The distribution of mutations was compared between uracil DNA glycosylase (Ung)-deficient and wild-type mice in endogenous Ig genes and in an Ig transgene [8].
• After combined oxygen-glucose deprivation, Ung(-/-) primary cortical neurons have increased vulnerability to cell death, which is associated with early mitochondrial dysfunction [3].
• 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 [3].

Biological context of Ung

• Inactivating Ung alone reduced mutations from A and T, suggesting that, depending on the DNA sequence, varying proportions of A,T mutations arise by error-prone long-patch base excision repair [9].
• C --> T mutagenesis and gamma-radiation sensitivity due to deficiency in the Smug1 and Ung DNA glycosylases [10].
• Mice deficient in the Ung uracil-DNA glycosylase have an increased level of uracil in their genome, consistent with a major role of Ung counteracting U:A base pairs arising by misincorporation of dUMP during DNA replication [11].
• Gene-targeted Ung(-/-) null mice remained tumour-free and showed no overt pathological phenotype up to approximately 12 months of age [11].
• Analysis of uracil-DNA glycosylases from the murine Ung gene reveals differential expression in tissues and in embryonic development and a subcellular sorting pattern that differs from the human homologues [12].

Anatomical context of Ung

• B-cell lymphomas arising in lymph nodes and spleen of aging mice deficient in the Ung DNA glycosylase were recovered, dispersed, grown in short-term culture, and CD19-positive B-cells retrieved and analysed [1].
• This suggests that Ung-proteins, directly or indirectly, have important functions in the immune system, not only in the process of antibody maturation, but also for production and functions of immunologically important cell types [2].
• In contrast, Ung1 was sorted both to nuclei and mitochondria [12].
• Ung2 is transported exclusively to the nucleus in NIH 3T3 cells as expected [12].
• Monoclonal B-cell hyperplasia and leukocyte imbalance precede development of B-cell malignancies in uracil-DNA glycosylase deficient mice [2].

Associations of Ung with chemical compounds

• Translocation also requires uracil DNA glycosylase (UNG), which removes uracil from DNA to create abasic sites that are then processed to double-strand breaks [13].
• On the other hand, DNA deamination hypothesis proposes that DNA cleavage is initiated by cytosine deamination in DNA, followed by uracil removal by uracil DNA glycosylase [14].
• We show that abrogation of Ung activity in P. aeruginosa and M. smegmatis confers upon them an increased mutator phenotype and sensitivity to reactive nitrogen intermediates generated by acidified nitrite [5].
• Interestingly, Ung(-/-) MEFs accumulate AP-sites as well as uracil in response to 5-FdUrd but not to 5-FU [15].
• METHODS: 129/Sv mice, uracil-DNA glycosylase-deficient (Ung-/-) mice, and Ung+/+ littermate mice were exposed to a folate-deficient diet for 3 months and then subjected to 30-minute middle cerebral artery (MCA) occlusion and reperfusion [16].

Regulatory relationships of Ung

• Interestingly, abrogation of Ung activity in M. smegmatis results in nearly a total abolition of their multiplication and a much-decreased residency in macrophages stimulated with interferon gamma [5].

Other interactions of Ung

• Finally, because in the absence of both Ung and Msh6, transition mutations from C and G likely are "footprints" of AID, the data show that the activity of AID is restricted drastically in vivo compared with AID in cell-free assays [9].
• However, an additive 10-fold increase in spontaneous C:G to T:A transitions in cells deficient in both Smug1 and Ung demonstrates that these enzymes have distinct and nonredundant roles in suppressing C --> T mutability at non-CpG sites [10].
• Levels of uracil DNA glycosylase and AP endonuclease in murine B- and T-lymphocytes do not change with age [17].
• To assess whether uracil DNA glycosylase and dUTP nucleotidohydrolase (dUTPase) can be involved in repair-type DNA synthesis associated to crossing-over or induced by UV and X-ray treatments, we have studied these enzyme activities in male mouse germ cells at specific stages of differentiation [18].
• Uracil DNA glycosylase and endonuclease G activities did not change with age in nucleus or mitochondria [19].

Analytical, diagnostic and therapeutic context of Ung

• Ung knockout mice generated by gene targeting are viable, fertile, and phenotypically normal and have regular mutation rates [3].
• Here we show by DNA footprinting analysis that MPG, but not UDG, bound to base-pair mismatches especially to less stable pyrimidine-pyrimidine pairs, without catalyzing detectable base cleavage [20].

References