Deoxyuracil in DNA and disease: Genomic signal or managed situation?

Abstract

Genomic instability is implicated in the etiology of several deleterious health outcomes including megaloblastic anemia, neural tube defects, and neurodegeneration. Uracil misincorporation and its repair are known to cause genomic instability by inducing DNA strand breaks leading to apoptosis, but there is emerging evidence that uracil incorporation may also result in broader modifications of gene expression, including: changes in transcriptional stalling, strand breakmediated transcriptional upregulation, and direct promoter inhibition. The factors that influence uracil levels in DNA are cytosine deamination, de novo thymidylate (dTMP) biosynthesis, salvage dTMP biosynthesis, dUTPase, and DNA repair. There is evidence that the nuclear localization of the enzymes in these pathways in mammalian cells may modify and/or control the levels of uracil accumulation into nuclear DNA. Uracil sequencing technologies demonstrate that uracil in DNA is not distributed stochastically across the genome, but instead shows patterns of enrichment. Nuclear localization of the enzymes that modify uracil in DNA may serve to change these patterns of enrichment in a tissue-specific manner, and thereby signal the genome in response to metabolic and/or nutritional state of the cell.

Base-Resolution Analysis of Deoxyuridine at the Genome Scale Based on the Artificial Incorporation Modified Nucleobase

“… 7 , 8 The misincorporation of uracil is a type of damage of the endogenous DNA resulting in genomic instability. 7 Contrarily, the cytosine deamination by AID in specific regions plays vital roles in several cellular processes, 9 and it is this dysregulation that is believed to cause diseases. 10 As in the case of the dynamic regulation of other epigenetic modifications, 11 uracil in the DNA could also be modulated and removed by several uracil DNA glycosylases (UDGs) to initiate the base excision repair (BER) pathway in mammalian cells.…”

The Essential Co-Option of Uracil-DNA Glycosylases by Herpesviruses Invites Novel Antiviral Design

“…Nevertheless, coding sequences and regulatory motifs are at risk if excessive levels of mutation should accrue [16]. There is, however, mounting evidence from recent uracil-sequencing technologies that DNA uracil may be a managed signal for tissue-specific gene regulation [17]. In that case, it is possible for relevant cellular programs utilising uracil to be usurped by viruses to their advantage or/and to the detriment of the cell.…”

Detection of Genomic Uracil Patterns

“…The thymine analogue uracil base has long been considered as an error to be excluded from the DNA; however, key experimental evidence has emerged supporting a more fine-tuned view on the potential impact of genomic uracil (for a detailed review, see [ 1 ]). The uracil base (U) can appear in DNA from three sources ( Figure 1 ).…”

“…Thymine-replacing incorporation is less harmful because the DNA coding potential is not changed, however, the missing methyl label from the uracil base as compared to thymine (T) might result in the perturbation of certain DNA binding regulatory functions [ 16 ]. Recently, genomic uracil was suggested as a potential epigenetic marker [ 1 , 17 ].…”

“…The biosynthetic pathways of pyrimidine nucleotides have evolved to keep an extremely low cellular dUTP/dTTP ratio to minimize the frequency of thymine-replacing uracil incorporation ( Figure 2 ) [ 1 ]. Within this network, some enzymes show strict substrate specificity, such as dCMP deaminase (DCTD) [ 51 , 52 ], deoxyuridine triphosphatase (dUTPase) [ 53 ], and thymidylate synthase (TS) [ 54 ], which are dedicated to efficiently catalyze specific reactions producing dUMP and dTMP, respectively ( Figure 2 ).…”