Abstract
The appearance of uracil in the deoxyuridine moiety of DNA is among the most frequently occurring genomic modifications. Three different routes can result in genomic uracil, two of which do not require specific enzymes: spontaneous cytosine deamination due to the inherent chemical reactivity of living cells, and thymine-replacing incorporation upon nucleotide pool imbalances. There is also an enzymatic pathway of cytosine deamination with multiple DNA (cytosine) deaminases involved in this process. In order to describe potential roles of genomic uracil, it is of key importance to utilize efficient uracil-DNA detection methods. In this review, we provide a comprehensive and critical assessment of currently available uracil detection methods with special focus on genome-wide mapping solutions. Recent developments in PCR-based and in situ detection as well as the quantitation of genomic uracil are also discussed.
Highlights
The thymine analogue uracil base has long been considered as an error to be excluded from the DNA; key experimental evidence has emerged supporting a more fine-tuned view on the potential impact of genomic uracil.The uracil base (U) can appear in DNA from three sources (Figure 1)
Cytosine deaminations result in uracil:guanine (U:G) mismatches that can be fixed as point mutations upon the replication in one of the daughter cells unless repaired by base excision repair (BER) or mismatch repair (MMR) mechanisms
Other apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) enzymes are involved in antiviral defense of the innate immune system [10,22], but overexpression and/or mistargeting of APOBEC deaminases may lead tumorigenesis, tumor progression, and drug resistance [10,23,24,25,26]
Summary
The thymine analogue uracil base has long been considered as an error to be excluded from the DNA; key experimental evidence has emerged supporting a more fine-tuned view on the potential impact of genomic uracil (for a detailed review, see [1]). Other apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) enzymes are involved in antiviral defense of the innate immune system [10,22], but overexpression and/or mistargeting of APOBEC deaminases may lead tumorigenesis, tumor progression, and drug resistance [10,23,24,25,26] Another particular example for uracil appearance in DNA occurs upon drug treatments by targeting thymidylate biosynthesis, where the massive thymine-replacing uracil incorporation and/or its activated repair by futile cycles eventually lead to cell cycle arrest, cellular senescence, or apoptosis [27,28,29]. We provide a comprehensive and critical assessment of the repertoire of available methods measuring uracil-containing DNA (U-DNA) in different contexts with a special focus on next-generation sequencing (NGS)-based genomewide mapping solutions
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